Inhibitors of protease-activated receptor-2

ABSTRACT

The present application relates to certain substituted imidazole compounds, pharmaceutical compositions containing them, and methods of using them, including methods for treating pain, musculoskeletal inflammation, neuroinflammatory disorders, airway inflammation, itch, dermatitis, colitis and related conditions.

RELATED APPLICATION INFORMATION

This is a continuation of U.S. patent application Ser. No. 16/300,641,filed Nov. 12, 2018, which is a 371 U.S. National Phase of InternationalApplication No. PCT/EP2017/061409, filed May 11, 2017, which claims thebenefit of U.S. Provisional Application No. 62/335,496, filed May 12,2016. The entire contents of each of the aforementioned applications areincorporated herein by reference in their entirety.

FIELD

The present application relates to the treatment or prevention ofconditions or disorders related to pain, musculoskeletal inflammationsuch as osteoarthritis, neuroinflammatory disorders, airwayinflammation, itch, dermatitis, colitis and related conditions withsubstituted imidazoles compounds, compositions containing them andmethods of using them.

BACKGROUND

The actions of Protease Activated Receptor-2 (PAR2) are thought to beinvolved in pain, musculoskeletal inflammation, neuroinflammatorydisorders, airway inflammation, itch, dermatitis, colitis and relatedconditions. The protease activated receptors are composed of four familymembers (PAR1, PAR2, PAR3 and PAR4), which are G-protein coupledreceptors activated by a proteolytic cleavage of the N-terminal regionof the receptor (Ramachandran, Hollenberg et al, Nature Reviews DrugDiscovery, 2012, 11 69-86). Upon proteolytic cleavage, the receptor thenis activated for second messenger activation and cellular responses.Many enzymes are known to cleave the N-terminal region of PAR receptorsto initiate this process such as thrombin, trypsin, mast cell tryptase,kallikreins and related enzymes in the inflammatory and coagulationcascades. Other ligands are known to activate the receptor, such asshort peptides like SLIGKV-NH2 (SEQ ID NO.: 2), SLIGLR-NH2 (SEQ ID NO.:3) or small molecule ligands such as GB-110 (Fairlie et al, Journal ofMedicinal Chemistry, 2013, 56, 7477-7497).

PAR2 expression has been shown to be increased in synovial lining,chondrocytes, and tissues in human rheumatoid arthritis and animalmodels of arthritis (Amiable, N. et al, Bone, 44, 1143-1150). PAR2 alsopotentiates signaling via channels such as TRPV1 (Dai, et al Journal ofInnate Immunology, 2010, 2, 495-504), a ligand-gated ion channelinvolved in inflammatory pain. PAR2 signaling is also known to sensitizeTRPV1 in vivo, resulting in thermal hyperalgesia.

The inhibition of PAR2 receptors is known to be responsible forinflammatory signaling pathways. In mice lacking the PAR2 receptor,there is a delayed onset of inflammation (Linder et al, Journal ofImmunology 2000, 165, 6504-6510). Other rodent PAR2 knockout studieshave demonstrated that PAR2 plays an important role in pathophysiologyof many disease conditions such as pain, musculoskeletal inflammationsuch as osteoarthritis, neuroinflammatory disorders, airwayinflammation, itch, dermatitis, colitis and related conditions (Fairlieet al, Journal of Medicinal Chemistry, 2013, 56, 7477-749). PAR2receptor antagonists such as GB88 have also been shown to blockinflammatory responses in vivo such as collagen-induced arthritis modelin rats (Fairlie et al, FASEB Journal, 2012, 26, 2877-2887).

PAR2 antagonists are thus thought likely to provide benefit to numerouspeople and to have a potential to alleviate pain and inflammationrelated conditions.

SUMMARY OF THE APPLICATION

This application provides a compound of formula (I),

or a pharmaceutically acceptable salt thereof, wherein:

-   R³ is —H or halogen (such as —F);-   X is N or CH;-   Y is C or N; and-   Z is C or N, wherein Y and Z are not both N, and-   (1) when both Z and Y are C, the bond “    ” is a double bond, and    -   R¹ is selected from alkyl (such as C₁₋₁₂-alkyl-, C₂₋₁₂-alkyl-,        or C₂₋₆-alkyl-, e.g., ethyl or propyl); alkenyl (such as        C₂₋₁₂-alkenyl- or C₂₋₆-alkenyl-, e.g.,

cycloalkyl (such as C₃₋₁₀-cycloalkyl- or C₃₋₆-cycloalkyl-, e.g.,cyclobutyl, cyclopentyl, or

cycloalkenyl (such as C₃₋₁₀-cycloalkenyl- or C₃₋₆-cycloalkenyl-, e.g.,

aryl (such as C₆₋₁₀-aryl-); heterocyclyl (such as 3- to 10-memberedheterocyclyl- or 3- to 6-membered heterocyclyl, e.g.,

wherein n is selected from 0-3); and heteroaryl (such as 5- to10-membered heteroaryl-, e.g.,

wherein n is selected from 0-3); wherein R¹ is substituted with 0-3 R,wherein each occurrence of R is independently selected from alkyl, suchas C₁₋₄alkyl (e.g., methyl, ethyl, or —CF₃); cycloalkyl; halo, such as—F, —Cl, or —Br (e.g., —Cl); —OH; alkoxy, such as methoxy; —CN;—NR^(a)R^(b); —N(R^(a))C(O) alkyl; —N(R^(a))CO₂alkyl; —N(R^(a))SO₂alkyl;—C(O)alkyl; —CO₂H; —CO₂alkyl; —CONR^(a)R^(b); —SO₂alkyl; and—SO₂NR^(a)R^(b); wherein R^(a) and R^(b) are independently for eachoccurrence H or alkyl;

-   -   R² is —H or -halogen (such as —F or —CO; or    -   R¹ and R² may be taken together with the atoms to which they are        bound to form a 3- to 10-membered aromatic or non-aromatic        monocyclic ring having 0-3 heteroatoms or heteroatom groups        independently selected from N, NH, O, S, SO, and SO₂, wherein        said ring is substituted with 0-3 R, and wherein said ring is        optionally fused to a C₆₋₁₀aryl, 5- to 10-membered heteroaryl,        C₃₋₁₀cycloalkyl, or a 3- to 10-membered heterocyclyl, wherein        said C₆₋₁₀aryl, 5- to 10-membered heteroaryl, C₃₋₁₀cycloalkyl,        or a 3- to 10-membered heterocyclyl is substituted with 0-3 R,        wherein each occurrence of R is independently selected from        alkyl, such as C₁₋₄alkyl (e.g., methyl, ethyl, propyl,        isopropyl, —CH₂CF₃ or —CF₃); cycloalkyl (e.g., cyclopropyl or

halo, such as —F, —Cl, or —Br (e.g., —Cl); —OH; alkoxy, such as methoxy;—CN; —NR^(a)R^(b); —N(R^(a))C(O) alkyl; —N(R^(a))CO₂alkyl;—N(R^(a))SO₂alkyl; —C(O)alkyl; —CO₂H; —CO₂alkyl; —CONR^(a)R^(b);—SO₂alkyl; and —SO₂NR^(a)R^(b); wherein R^(a) and R^(b) areindependently for each occurrence H or alkyl; or

-   (2) when one of Z and Y is N and the other is C, the bond “    ” is a single bond, and R¹ and R² are taken together with the atoms    to which they are bound to form a 3- to 10-membered aromatic or    non-aromatic monocyclic ring having 0-3 heteroatoms or heteroatom    groups independently selected from N, NH, O, S, SO, and SO₂, wherein    said ring is substituted with 0-3 R, and wherein said ring is    optionally fused to a C₆₋₁₀aryl, 5- to 10-membered heteroaryl,    C₃₄₀cycloalkyl, or a 3- to 10-membered heterocyclyl, wherein said    C₆₋₁₀aryl, 5- to 10-membered heteroaryl, C₃₄₀cycloalkyl, or a 3- to    10-membered heterocyclyl is substituted with 0-3 R, wherein each    occurrence of R is independently selected from alkyl, such as    C₁₋₄alkyl (e.g., methyl, ethyl, propyl, isopropyl, —CH₂CF₃ or —CF₃);    cycloalkyl (e.g., cyclopropyl or

halo, such as —F, —Cl, or —Br (e.g., —Cl); —OH; alkoxy, such as methoxy;—CN; —NR^(a)R^(b); —N(R^(a))C(O) alkyl; —N(R^(a))CO₂alkyl;—N(R^(a))SO₂alkyl; —C(O)alkyl; —CO₂H; —CO₂alkyl; —CONR^(a)R^(b);—SO₂alkyl; and —SO₂NR^(a)R^(b); wherein R^(a) and R^(b) areindependently for each occurrence H or alkyl;provided that when R¹ is methyl and X is CH, R² and R³ are not both —H.In some embodiments of the forgoing, when R¹ is methyl and X is CH, R³is —F.

In certain embodiments, R³ is —H. In certain embodiments, R³ is —F.

In certain embodiments, X is CH. In certain embodiments, X is N.

In certain embodiments, both Z and Y are C and the bond “

” is a double bond. In certain embodiments, both Z and Y are C, the bond“

” is a double bond and the compound can be represented by formula (I-A):

or a pharmaceutically acceptable salt thereof, wherein:

-   X is N or CH;-   R¹ is selected from alkyl (such as C₁₋₁₂-alkyl-, C₂₋₁₂-alkyl-, or    C₂₋₆-alkyl-, e.g., ethyl or propyl); alkenyl (such as    C₂₋₁₂-alkenyl-, or C₂₋₆-alkenyl-, e.g.,

cycloalkyl (such as C₃₋₁₀-cycloalkyl- or C₃₋₆-cycloalkyl-, e.g.,cyclobutyl, cyclopentyl, or

cycloalkenyl (such as C₃₋₁₀-cycloalkenyl- or C₃₋₆-cycloalkenyl-, e.g.,

aryl (such as C₆₋₁₀-aryl-); heterocyclyl (such as 3- to 10-memberedheterocyclyl- or 3- to 6-membered heterocyclyl, e.g.,

wherein n is selected from 0-3); and heteroaryl (such as 5- to10-membered heteroaryl-, e.g.,

wherein n is selected from 0-3); wherein R¹ is substituted with 0-3 R,wherein each occurrence of R is independently selected from alkyl, suchas C₁₋₄alkyl (e.g., methyl, ethyl, or —CF₃); cycloalkyl; halo, such as—F, —Cl, or —Br (e.g., —Cl); —OH; alkoxy, such as methoxy; —CN;—NR^(a)R^(b); —N(R^(a))C(O) alkyl; —N(R^(a))CO₂alkyl; —N(R^(a))SO₂alkyl;—C(O)alkyl; —CO₂H; —CO₂alkyl; —CONR^(a)R^(b); —SO₂alkyl; and—SO₂NR^(a)R^(b); wherein R^(a) and R^(b) are independently for eachoccurrence H or alkyl;

-   R² is —H or -halogen (such as —F or —Cl); or-   R¹ and R² may be taken together with the atoms to which they are    bound to form a 3- to 10-membered aromatic or non-aromatic    monocyclic ring having 0-3 heteroatoms or heteroatom groups    independently selected from N, NH, O, S, SO, and SO₂, wherein said    ring is substituted with 0-3 R, and wherein said ring is optionally    fused to a C₆₋₁₀aryl, 5- to 10-membered heteroaryl, C₃₋₁₀cycloalkyl,    or a 3- to 10-membered heterocyclyl, wherein said C₆₋₁₀aryl, 5- to    10-membered heteroaryl, C₃₋₁₀cycloalkyl, or a 3- to 10-membered    heterocyclyl is substituted with 0-3 R, wherein each occurrence of R    is independently selected from alkyl, such as C₁₋₄alkyl (e.g.,    methyl, ethyl, propyl, isopropyl, —CH₂CF₃ or —CF₃); cycloalkyl    (e.g., cyclopropyl or

halo, such as —F, —Cl, or —Br (e.g., —Cl); —OH; alkoxy, such as methoxy;—CN; —NR^(a)R^(b); —N(R^(a))C(O) alkyl; —N(R^(a))CO₂alkyl;—N(R^(a))SO₂alkyl; —C(O)alkyl; —CO₂H; —CO₂alkyl; —CONR^(a)R^(b);—SO₂alkyl; and —SO₂NR^(a)R^(b); wherein R^(a) and R^(b) areindependently for each occurrence H or alkyl; and R³ is —H or halogen(such as —F);provided that when R¹ is methyl and X is CH, R² and R³ are not both —H.In some embodiments of the forgoing, when R¹ is methyl and X is CH, R³is —F.

In certain embodiments wherein one of Z and Y is N and the other is C,the compound can be represented by formula (I-B):

or a pharmaceutically acceptable salt thereof, wherein:

-   X is N or CH;-   R¹ and R² are taken together with the atoms to which they are bound    to form a 3- to 10-membered aromatic or non-aromatic monocyclic ring    having 0-3 heteroatoms or heteroatom groups independently selected    from N, NH, O, S, SO, and SO₂, wherein said ring is substituted with    0-3 R, and wherein said ring is optionally fused to a C₆₋₁₀aryl, 5-    to 10-membered heteroaryl, C₃₋₁₀cycloalkyl, or a 3- to 10-membered    heterocyclyl, wherein said C₆₋₁₀aryl, 5- to 10-membered heteroaryl,    C₃₋₁₀cycloalkyl, or a 3- to 10-membered heterocyclyl is substituted    with 0-3 R, wherein each occurrence of R is independently selected    from alkyl, such as C₁₋₄alkyl (e.g., methyl, ethyl, propyl,    isopropyl, —CH₂CF₃ or —CF₃); cycloalkyl (e.g., cyclopropyl or

halo, such as —F, —Cl, or —Br (e.g., —Cl); —OH; alkoxy, such as methoxy;—CN; —NR^(a)R^(b); —N(R^(a))C(O) alkyl; —N(R^(a))CO₂alkyl;—N(R^(a))SO₂alkyl; —C(O)alkyl; —CO₂H; —CO₂alkyl; —CONR^(a)R^(b);—SO₂alkyl; and —SO₂NR^(a)R^(b); wherein R^(a) and R^(b) areindependently for each occurrence H or alkyl; and

-   R³ is —H or halogen (such as —F).

In certain embodiments, Y is C and Z is N and the bond “

” is a single bond. In certain embodiments, Y is N and Z is C and thebond “

” is a single bond.

In another aspect, the present application provides a compound thatbinds to an allosteric site of a PAR2 polypeptide comprising an aminoacid sequence set forth in SEQ ID NO.: 1, wherein the compound interactswith one or more amino acid residues selected from the group consistingof Asp 228, Lys 131, His 135, and Tyr 82 of SEQ ID NO.: 1. In someembodiments, the compound binds to an allosteric site of a PAR2polypeptide comprising an amino acid sequence set forth in SEQ ID NO.:1, wherein the compound interacts with amino acid residues Asp 228, Lys131, and His 135 of SEQ ID NO.: 1. In some embodiments, the compoundbinds to an allosteric site of a PAR2 polypeptide comprising an aminoacid sequence set forth in SEQ ID NO.: 1, wherein the compound interactswith amino acid residues Asp 228, Lys 131, His 135, and Tyr 82 of SEQ IDNO.: 1. In some embodiments, such a compound is an antagonist of PAR2.In some embodiments, such a compound is a small molecule (e.g., a smallmolecule antagonist). In certain embodiments of the forgoing, thecompound has a structure of formula (I), (I-A), or (I-B), or apharmaceutically acceptable salt thereof.

In another aspect, the present application provides a compound thatbinds to an allosteric site of PAR2 polypeptide comprising an amino acidsequence set forth in SEQ ID NO.: 1, wherein said compound has a targetdissociative half life (t_(1/2)) of greater than 10 minutes. In someembodiments, the compound binds to an allosteric site of PAR2polypeptide comprising an amino acid sequence set forth in SEQ ID NO.:1, wherein said compound has a target dissociative half life (t_(1/2))selected from over 3000 minutes, 10 to 3000 minutes, 10 to 2000 minutes,10 to 1000 minutes, 10 to 900 minutes, 10 to 800 minutes, 10 to 700minutes, 10 to 600 minutes, 10 to 500 minutes, 10 to 400 minutes, 10 to300 minutes, 10 to 200 minutes, 10 to 100 minutes, 10 to 50 minutes, 10to 40 minutes, 10 to 30 minutes, and 10 to 20 minutes. In someembodiments, such a compound has a target dissociative half life of 10to 200 minutes. In some embodiments of the forgoing, the compound bindsto an allosteric site of a PAR2 polypeptide comprising an amino acidsequence set forth in SEQ ID NO.: 1, wherein the compound interacts withone or more amino acid residues selected from the group consisting ofAsp 228, Lys 131, His 135, and Tyr 82 of SEQ ID NO.: 1. In someembodiments, the compound interacts with amino acid residues Asp 228,Lys 131, and His 135 of SEQ ID NO.: 1. In some embodiments, the compoundinteracts with amino acid residues Asp 228, Lys 131, His 135, and Tyr 82of SEQ ID NO.: 1. In certain embodiments, the dissociative half life isdetermined in either a FLPR dissociation assay, surface plasmonresonance assay or radiochemical binding assay. In some embodiments,such a compound is an antagonist of PAR2. In some embodiments, such acompound is a small molecule (e.g., a small molecule antagonist). Insome embodiments of the forgoing, the compound has a structure offormula (I), (I-A), or (I-B), or a pharmaceutically acceptable saltthereof.

In certain embodiments, this application provides a pharmaceuticalcomposition, comprising at least one compound described herein, or apharmaceutically acceptable salt thereof. Pharmaceutical compositions asdescribed herein may further comprise a pharmaceutically acceptableexcipient. In certain embodiments, this application also provides acompound described herein or a pharmaceutically acceptable salt thereof,or a composition comprising of any of the foregoing for use as amedicament.

In another aspect, this application provides methods of treating adisease or disorder mediated by PAR2 activity, such as those describedherein, comprising administering to a subject in need of such treatment,such as a patient, an effective amount of at least one compounddescribed herein or a pharmaceutically acceptable salt thereof in adose, at a frequency, and for a duration to provide a beneficial effectto the subject.

In certain embodiments, this application provides the use of a compounddescribed herein, or a pharmaceutically acceptable salt thereof, or acomposition comprising of any of the foregoing in the preparation of amedicament for the treatment of diseases or disorders regulated by PAR2activity, and the use of such compounds and salts for treatment of suchdiseases and disorders.

In certain embodiments, this application provides a method of treating adisease or disorder in a subject, such as a patient, comprisingmodulating PAR2, wherein the modulation of PAR2 comprises administeringto the subject at least one compound described herein, or apharmaceutically acceptable salt thereof, or a composition comprising ofany of the foregoing, in a dose, at a frequency, and for a duration toprovide a beneficial effect to the subject patient. In certain suchembodiments, the disease or disorder is selected from the groupconsisting of pain, musculoskeletal inflammation (such asosteoarthritis), neuroinflammatory disorders, airway inflammation, itch,dermatitis, or colitis. In certain embodiments, the disease or disorderis osteoarthritis.

In certain embodiments, this application provides a method of modulatingthe activity of PAR2, comprising contacting a cell comprising the PAR2with an effective amount of at least one compound described herein, or apharmaceutically acceptable salt thereof, or a composition comprisingany one of the foregoing.

In certain embodiments, this application describes a method ofmodulating the activity of a PAR2 receptor, comprising contacting a cellcomprising the PAR2 receptor with an effective amount of at least onecompound described herein or a pharmaceutically acceptable salt thereof,and/or with at least one compound or pharmaceutical composition asdescribed herein. In certain embodiments of the foregoing, thecontacting is in vitro, ex vivo, or in vivo.

Additional embodiments, features, and advantages of the application willbe apparent from the following detailed description and through practiceof the embodiments described in this application.

DETAILED DESCRIPTION OF THE FIGURES

FIG. 1 shows PAR1 crystal structure bound to Vorapaxar compared to PAR2crystal structure bound to the compound of Example 3.

FIG. 2 shows PAR2 crystal structure in complex with the compound ofExample 3.

FIG. 3 shows Protein-ligand interactions with the compound Example 3based on PAR2 crystal structure.

DETAILED DESCRIPTION

The present applicant provides a compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

-   R³ is —H or halogen (such as —F);-   X is N or CH;-   Y is C or N; and-   Z is C or N, wherein Y and Z are not both N, and-   (1) when both Z and Y are C, the bond “    ” is a double bond, and    -   R¹ is selected from alkyl (such as C₁₋₁₂-alkyl-, C₂₋₁₂-alkyl-,        or C₂₋₆-alkyl-, e.g., ethyl or propyl); alkenyl (such as        C₂₋₁₂-alkenyl- or C₂₋₆-alkenyl-, e.g.,

cycloalkyl (such as C₃₋₁₀-cycloalkyl- or C₃₋₆-cycloalkyl-, e.g.,cyclobutyl, cyclopentyl, or

cycloalkenyl (such as C₃₋₁₀-cycloalkenyl- or C₃₋₆-cycloalkenyl-, e.g.,

aryl (such as C₆₋₁₀-aryl-); heterocyclyl (such as 3- to 10-memberedheterocyclyl- or 3- to 6-membered heterocyclyl, e.g.,

wherein n is selected from 0-3); and heteroaryl (such as 5- to10-membered heteroaryl- or as 5- to 6-membered heteroaryl-, e.g.,

wherein n is selected from 0-3); wherein R¹ is substituted with 0-3 R,wherein each occurrence of R is independently selected from alkyl, suchas C₁₋₄alkyl (e.g., methyl, ethyl, or —CF₃); cycloalkyl; halo, such as—F, —Cl, or —Br (e.g., —Cl); —OH; alkoxy, such as methoxy; —CN;—NR^(a)R^(b); —N(R^(a))C(O) alkyl; —N(R^(a))CO₂alkyl; —N(R^(a))SO₂alkyl;—C(O)alkyl; —CO₂H; —CO₂alkyl; —CONR^(a)R^(b); —SO₂alkyl; and—SO₂NR^(a)R^(b); wherein R^(a) and R^(b) are independently for eachoccurrence H or alkyl;

-   -   R² is —H or -halogen (such as —F or —Cl); or    -   R¹ and R² may be taken together with the atoms to which they are        bound to form a 3- to 10-membered aromatic or non-aromatic        monocyclic ring having 0-3 heteroatoms or heteroatom groups        independently selected from N, NH, O, S, SO, and SO₂, wherein        said ring is substituted with 0-3 R, and wherein said ring is        optionally fused to a C₆₋₁₀aryl, 5- to 10-membered heteroaryl,        C₃₋₁₀cycloalkyl, or a 3- to 10-membered heterocyclyl, wherein        said C₆₋₁₀aryl, 5- to 10-membered heteroaryl, C₃₋₁₀cycloalkyl,        or a 3- to 10-membered heterocyclyl is substituted with 0-3 R,        wherein each occurrence of R is independently selected from        alkyl, such as C₁₋₄alkyl (e.g., methyl, ethyl, propyl,        isopropyl, —CH₂CF₃ or —CF₃); cycloalkyl (e.g., cyclopropyl or

halo, such as —F, —Cl, or —Br (e.g., —Cl); —OH; alkoxy, such as methoxy;—CN; —NR^(a)R^(b); —N(R^(a))C(O) alkyl; —N(R^(a))CO₂alkyl;—N(R^(a))SO₂alkyl; —C(O)alkyl; —CO₂H; —CO₂alkyl; —CONR^(a)R^(b);—SO₂alkyl; and —SO₂NR^(a)R^(b); wherein R^(a) and R^(b) areindependently for each occurrence H or alkyl; or

-   (2) when one of Z and Y is N and the other is C, the bond “    ” is a single bond, and R¹ and R² are taken together with the atoms    to which they are bound to form a 3- to 10-membered aromatic or    non-aromatic monocyclic ring having 0-3 heteroatoms or heteroatom    groups independently selected from N, NH, O, S, SO, and SO₂, wherein    said ring is substituted with 0-3 R, and wherein said ring is    optionally fused to a C₆₋₁₀aryl, 5- to 10-membered heteroaryl,    C₃₋₁₀cycloalkyl, or a 3- to 10-membered heterocyclyl, wherein said    C₆₋₁₀aryl, 5- to 10-membered heteroaryl, C₃₋₁₀cycloalkyl, or a 3- to    10-membered heterocyclyl is substituted with 0-3 R, wherein each    occurrence of R is independently selected from alkyl, such as    C₁₋₄alkyl (e.g., methyl, ethyl, propyl, isopropyl, —CH₂CF₃ or —CF₃);    cycloalkyl (e.g., cyclopropyl or

halo, such as —F, —Cl, or —Br (e.g., —Cl); —OH; alkoxy, such as methoxy;—CN; —NR^(a)R^(b); —N(R^(a))C(O) alkyl; —N(R^(a))CO₂alkyl;—N(R^(a))SO₂alkyl; —C(O)alkyl; —CO₂H; —CO₂alkyl; —CONR^(a)R^(b);—SO₂alkyl; and —SO₂NR^(a)R^(b); wherein R^(a) and R^(b) areindependently for each occurrence H or alkyl;provided that when R¹ is methyl and X is CH, R² and R³ are not both —H.In certain embodiments, when R¹ is methyl and X is CH, R³ is —F.

In certain embodiments, X is CH. In certain embodiments, X is N.

In certain embodiments, R³ is —H. In certain embodiments, R³ is —F.

In certain embodiments, both Z and Y are C and the bond “

” is a double bond. In certain embodiments, both Z and Y are C, the bond“

” is a double bond, and the compound can be represented by formula(I-A):

or a pharmaceutically acceptable salt thereof, wherein:

-   X is N or CH;-   R¹ is selected from alkyl (such as C₁₋₁₂-alkyl-, C₂₋₁₂-alkyl-, or    C₂₋₆-alkyl-, e.g., ethyl or propyl); alkenyl (such as    C₂₋₁₂-alkenyl-, or C₂₋₆-alkenyl-, e.g.,

cycloalkyl (such as C₃₋₁₀-cycloalkyl- or C₃₋₆-cycloalkyl-, e.g.,cyclobutyl, cyclopentyl, or

cycloalkenyl (such as C₃₋₁₀-cycloalkenyl- or C₃₋₆-cycloalkenyl-, e.g.,

aryl (such as C₆₋₁₀-aryl-); heterocyclyl (such as 3- to 10-memberedheterocyclyl- or 3- to 6-membered heterocyclyl, e.g.,

wherein n is selected from 0-3); and heteroaryl (such as 5- to10-membered heteroaryl-, e.g.,

wherein n is selected from 0-3); wherein R¹ is substituted with 0-3 R,wherein each occurrence of R is independently selected from alkyl, suchas C₁₋₄alkyl (e.g., methyl, ethyl, or —CF₃); cycloalkyl; halo, such as—F, —Cl, or —Br (e.g., —Cl); —OH; alkoxy, such as methoxy; —CN;—NR^(a)R^(b); —N(R^(a))C(O) alkyl; —N(R^(a))CO₂alkyl; —N(R^(a))SO₂alkyl;—C(O)alkyl; —CO₂H; —CO₂alkyl; —CONR^(a)R^(b); —SO₂alkyl; and—SO₂NR^(a)R^(b); wherein R^(a) and R^(b) are independently for eachoccurrence H or alkyl;

-   R² is —H or -halogen (such as —F or —Cl); or-   R¹ and R² may be taken together with the atoms to which they are    bound to form a 3- to 10-membered aromatic or non-aromatic    monocyclic ring having 0-3 heteroatoms or heteroatom groups    independently selected from N, NH, O, S, SO, and SO₂, wherein said    ring is substituted with 0-3 R, and wherein said ring is optionally    fused to a C₆₋₁₀aryl, 5- to 10-membered heteroaryl, C₃₋₁₀cycloalkyl,    or a 3- to 10-membered heterocyclyl, wherein said C₆₋₁₀aryl, 5- to    10-membered heteroaryl, C₃₋₁₀cycloalkyl, or a 3- to 10-membered    heterocyclyl is substituted with 0-3 R, wherein each occurrence of R    is independently selected from alkyl, such as C₁₋₄alkyl (e.g.,    methyl, ethyl, propyl, isopropyl, —CH₂CF₃ or —CF₃); cycloalkyl    (e.g., cyclopropyl or

halo, such as —F, —Cl, or —Br (e.g., —Cl); —OH; alkoxy, such as methoxy;—CN; —NR^(a)R^(b); —N(R^(a))C(O) alkyl; —N(R^(a))CO₂alkyl;—N(R^(a))SO₂alkyl; —C(O)alkyl; —CO₂H; —CO₂alkyl; —CONR^(a)R^(b);—SO₂alkyl; and —SO₂NR^(a)R^(b); wherein R^(a) and R^(b) areindependently for each occurrence H or alkyl; and

-   R³ is —H or halogen (such as —F);-   provided that when R¹ is methyl and X is CH, R² and R³ are not both    —H. In some embodiments of the forgoing, when R¹ is methyl and X is    CH, R³ is —F.

In certain embodiments, X is CH. In certain embodiments, X is N.

In certain embodiments, R³ is —H. In certain embodiments, R³ is —F.

In certain embodiments of compounds of formula (I) or (I-A), R¹ is C₁₋₁₂alkyl that is optionally substituted with 0-3 R. In some embodiments, R¹is C₂₋₁₂ alkyl that is optionally substituted with 0-3 R. In someembodiments, R¹ is C₂₋₆ alkyl that is optionally substituted with 0-3 R.In some embodiments, R¹ is a linear or branched C₃₋₆ alkyl that isoptionally substituted with 0-3 R. In some of the above embodiments, R¹is unsubstituted. In some embodiments, R¹ is ethyl or propyl. In someembodiments, R¹ is propyl.

In certain embodiments of compounds of formula (I) or (I-A), R¹ is C₂₋₁₂alkenyl that is optionally substituted with 0-3 R. In some embodiments,R¹ is C₂₋₆ alkenyl that is optionally substituted with 0-3 R. In someembodiments, R¹ is a linear or branched C₃₋₆ alkenyl that is optionallysubstituted with 0-3 R. In some of the above embodiments, R¹ isunsubstituted. In some embodiments, R¹ is

In certain embodiments of compounds of formula (I) or (I-A), R¹ isC₃₋₁₀-cycloalkyl- that is optionally substituted with 0-3 R. In someembodiments, R¹ is C₃₋₆-cycloalkyl- that is optionally substituted with0-3 R. In some embodiments, R¹ is selected from cyclobutyl, cyclopentyl,and

wherein R¹ is optionally substituted with 0-3 R. In some of the aboveembodiments, R¹ is unsubstituted.

In certain embodiments of compounds of formula (I) or (I-A), R¹ isC₃₋₁₀-cycloalkenyl- that is optionally substituted with 0-3 R. In someembodiments, R¹ is C₃₋₆-cycloalkenyl- that is optionally substitutedwith 0-3 R. In some embodiments, R¹ is

that is optionally substituted with 0-3 R. In some of the aboveembodiments, R¹ is unsubstituted.

In certain embodiments of compounds of formula (I) or (I-A), R¹ is 3- to10-membered heterocyclyl- that is optionally substituted with 0-3 R. Insome embodiments, R¹ is 3- to 6-membered heterocyclyl- that isoptionally substituted with 0-3 R. In some embodiments, R¹ is selectedfrom:

wherein n is 0-3. In some of the above embodiments, R¹ is unsubstituted.In some of the above embodiments, each occurrence of R is independentlyselected from: C₁₋₃ alkyl (such as -Me) and halogen (such as —F). Insome embodiments, R¹ is selected from:

In certain embodiments of compounds of formula (I) or (I-A), R¹ is 5- to10-membered heteroaryl- that is optionally substituted with 0-3 R. Insome embodiments, R¹ is 5- or 6-membered heteroaryl- that is optionallysubstituted with 0-3 R. In some embodiments, R¹ is selected from:

wherein n is 0-3. In some embodiments, R¹ is unsubstituted, and isselected from:

In certain embodiments of compounds of formula (I) or (I-A), R² is —H or-halogen. In some embodiments, R² is —H. In some embodiments, R² is —For —Cl.

In certain embodiments of compounds of formula (I) or (I-A), R¹ and R²are taken together with the atoms to which they are bound to form a 3-to 10-membered aromatic or non-aromatic monocyclic ring having 0-3heteroatoms or heteroatom groups independently selected from N, NH, O,S, SO, and SO₂, wherein said ring is substituted with 0-3 R, and whereinsaid ring is optionally fused to a C₆₋₁₀aryl, 5- to 10-memberedheteroaryl, C₃₋₁₀cycloalkyl, or a 3- to 10-membered heterocyclyl,wherein said C₆₋₁₀aryl, 5- to 10-membered heteroaryl, C₃₋₁₀cycloalkyl,or a 3- to 10-membered heterocyclyl is substituted with 0-3 R. In someof the above embodiments, the structure

of formula (I) or the structure

of formula (I-A) is selected from:

wherein R⁵ is —H or —C₁₋₃alkyl, n is selected from 0-3. In some of theseembodiments, R⁵ is -Me or -Et. In some of the above embodiments, eachoccurrence of R is independently selected from: C₁₋₄alkyl,C₃₋₆cycloalkyl, and halo. In some of the above embodiments, eachoccurrence of R is independently selected from: methyl, ethyl, propyl,isopropyl, —CH₂CF₃, —CF₃, cyclopropyl,

—F, —Cl, and —Br, for example, methyl, ethyl, —CH₂CF₃, cyclopropyl, and

In some embodiments, the structure

of formula (I) or the structure

of formula (I-A) is selected from:

In certain embodiments wherein one of Z and Y is N and the other is C,the compound can be represented by formula (I-B):

or a pharmaceutically acceptable salt thereof, wherein:

-   X is N or CH;-   R¹ and R² are taken together with the atoms to which they are bound    to form a 3- to 10-membered aromatic or non-aromatic monocyclic ring    having 0-3 heteroatoms or heteroatom groups independently selected    from N, NH, O, S, SO, and SO₂, wherein said ring is substituted with    0-3 R, and wherein said ring is optionally fused to a C₆₋₁₀aryl, 5-    to 10-membered heteroaryl, C₃₄₀cycloalkyl, or a 3- to 10-membered    heterocyclyl, wherein said C₆₋₁₀aryl, 5- to 10-membered heteroaryl,    C₃₄₀cycloalkyl, or a 3- to 10-membered heterocyclyl is substituted    with 0-3 R, wherein each occurrence of R is independently selected    from alkyl, such as C₁₋₄alkyl (e.g., methyl, ethyl, propyl,    isopropyl, —CH₂CF₃ or —CF₃); cycloalkyl (e.g., cyclopropyl or

halo, such as —F, —Cl, or —Br (e.g., —Cl); —OH; alkoxy, such as methoxy;—CN; —NR^(a)R^(b); —N(R^(a))C(O) alkyl; —N(R^(a))CO₂alkyl;—N(R^(a))SO₂alkyl; —C(O)alkyl; —CO₂H; —CO₂alkyl; —CONR^(a)R^(b);—SO₂alkyl; and —SO₂NR^(a)R^(b); wherein R^(a) and R^(b) areindependently for each occurrence H or alkyl;

-   R³ is —H or halogen (such as —F).

In certain embodiments, Y is C and Z is N and the bond “

” is a single bond. In certain embodiments, Y is N and Z is C and thebond “

” is a single bond.

In certain embodiments, X is CH. In certain embodiments, X is N.

In certain embodiments, R³ is —H. In certain embodiments, R³ is —F.

In certain embodiments of compounds of formula (I) or (I-B), thestructure

is selected from:

wherein n is selected from 0-3. In some of these embodiments, eachoccurrence of R is independently selected from: C₁₋₄alkyl,C₃₋₆cycloalkyl, and halo. In some embodiments, each occurrence of R isindependently selected from: methyl, ethyl, propyl, isopropyl, —CH₂CF₃,—CF₃, cyclopropyl,

—F, —Cl, and —Br, such as methyl, ethyl, isopropyl, cyclopropyl, and—Cl. In some embodiments, the structure

of formula (I) or (I-B) is selected from:

In certain embodiments, the compound of the present application isselected from:

and pharmaceutically acceptable salts thereof.

An example of a compound of the specification is:

-   (4-Fluoro-2-propylphenyl)(1H-imidazol-2-yl)methanol;-   (R)-(4-fluoro-2-propylphenyl)(1H-imidazol-2-yl)methanol;-   (S)-(4-Fluoro-2-propylphenyl)(1H-imidazol-2-yl)methanol;-   (2-Cyclopentenylphenyl)(1H-imidazol-2-yl)methanol;-   (2-Cyclopentenyl-4-fluorophenyl)(1H-imidazol-2-yl)methanol;-   (2-Cyclopentyl-4-fluorophenyl)(1H-imidazol-2-yl)methanol;-   (2-Cyclobutyl-4-fluorophenyl)(1H-imidazol-2-yl)methanol;-   (E)-(4-Fluoro-2-(prop-1-enyl)phenyl)(1H-imidazol-2-yl)methanol;-   (Z)-(4-Fluoro-2-(prop-1-enyl)phenyl)(1H-imidazol-2-yl)methanol;-   (3,4-Difluoro-2-propylphenyl)(1H-imidazol-2-yl)methanol;-   (R)-(3,4-Difluoro-2-propylphenyl)(1H-imidazol-2-yl)methanol;-   (S)-(3,4-Difluoro-2-propylphenyl)(1H-imidazol-2-yl)methanol;-   (3-Chloro-2-propylphenyl)(1H-imidazol-2-yl)methanol;-   (4-Fluoro-2-(pyrrolidin-1-yl)phenyl)(1H-imidazol-2-yl)methanol;-   (R)-(4-Fluoro-2-(pyrrolidin-1-yl)phenyl)(1H-imidazol-2-yl)methanol;-   (S)-(4-Fluoro-2-(pyrrolidin-1-yl)phenyl)(1H-imidazol-2-yl)methanol;-   (2-(2,5-dihydro-1H-pyrrol-1-yl)-4-fluorophenyl)(1H-imidazol-2-yl)methanol;-   (R)-(2-(2,5-dihydro-1H-pyrrol-1-yl)-4-fluorophenyl)(1H-imidazol-2-yl)methanol;-   (S)-(2-(2,5-dihydro-1H-pyrrol-1-yl)-4-fluorophenyl)(1H-imidazol-2-yl)methanol;-   (2-(Azetidin-1-yl)-4-fluorophenyl)(1H-imidazol-2-yl)methanol;-   (3-Chloro-2-(1H-pyrazol-1-yl)phenyl)(1H-imidazol-2-yl)methanol;-   (3,4-Difluoro-2-(1H-pyrazol-1-yl)phenyl)(1H-imidazol-2-yl)methanol;-   (4-Fluoro-2-(1H-pyrazol-1-yl)phenyl)(1H-imidazol-2-yl)methanol;-   (4-Fluoro-2-(3-fluoro-3-methylazetidin-1-yl)phenyl)(1H-imidazol-2-yl)methanol;-   (4-Fluoro-2-(3-methylazetidin-1-yl)phenyl)(1H-imidazol-2-yl)methanol;-   (4-Fluoro-2-((S)-3-fluoropyrrolidin-1-yl)phenyl)(1H-imidazol-2-yl)methanol;-   (4-Fluoro-2-((R)-3-fluoropyrrolidin-1-yl)phenyl)(1H-imidazol-2-yl)methanol;-   (2-(3,3-Difluoropyrrolidin-1-yl)-4-fluorophenyl)(1H-imidazol-2-yl)methanol;-   (4-Fluoro-2-((R)-3-methylpyrrolidin-1-yl)phenyl)(1H-imidazol-2-yl)methanol;-   (2-(3-Azabicyclo[3.1.0]hexan-3-yl)-4-fluorophenyl)(1H-imidazol-2-yl)methanol;-   (2-(Bicyclo[3.1.0]hexan-1-yl)-4-fluorophenyl)(1H-imidazol-2-yl)methanol;-   (4-Fluoro-2-(oxazol-4-yl)phenyl)(1H-imidazol-2-yl)methanol;-   (4-Fluoro-2-(thiazol-4-yl)phenyl)(1H-imidazol-2-yl)methanol;-   (3-Ethyl-8-fluoroindolizin-5-yl)(1H-imidazol-2-yl)methanol;-   (R)-(3-Ethyl-8-fluoroindolizin-5-yl)(1H-imidazol-2-yl)methanol;-   (S)-(3-Ethyl-8-fluoroindolizin-5-yl)(1H-imidazol-2-yl)methanol;-   (8-Fluoro-3-methylindolizin-5-yl)(1H-imidazol-2-yl)methanol;-   (8-Fluoro-3-isopropylindolizin-5-yl)(1H-imidazol-2-yl)methanol;-   (3-Cyclopropyl-8-fluoroindolizin-5-yl)(1H-imidazol-2-yl)methanol;-   (3-Ethyl-7-fluorobenzofuran-4-yl)(1H-imidazol-2-yl)methanol;-   (R)-(3-Ethyl-7-fluorobenzofuran-4-yl)(1H-imidazol-2-yl)methanol;-   (S)-(3-Ethyl-7-fluorobenzofuran-4-yl)(1H-imidazol-2-yl)methanol;-   (3-Cyclopropyl-7-fluorobenzofuran-4-yl)(1H-imidazol-2-yl)methanol;-   (R)-(3-Cyclopropyl-7-fluorobenzofuran-4-yl)(1H-imidazol-2-yl)methanol;-   (S)-(3-Cyclopropyl-7-fluorobenzofuran-4-yl)(1H-imidazol-2-yl)methanol;-   (7-Fluoro-3-(2,2,2-trifluoroethyl)benzofuran-4-yl)(1H-imidazol-2-yl)methanol;-   (R)-(7-fluoro-3-(2,2,2-trifluoroethyl)benzofuran-4-yl)(1H-imidazol-2-yl)methanol;-   (S)-(7-fluoro-3-(2,2,2-trifluoroethyl)benzofuran-4-yl)(1H-imidazol-2-yl)methanol;-   (3-Ethyl-7-fluorobenzo[b]thiophen-4-yl)(1H-imidazol-2-yl)methanol;-   (R)-(3-Ethyl-7-fluorobenzo[b]thiophen-4-yl)(1H-imidazol-2-yl)methanol;-   (S)-(3-Ethyl-7-fluorobenzo[b]thiophen-4-yl)(1H-imidazol-2-yl)methanol;-   (7-Fluoro-3-methylbenzofuran-4-yl)(1H-imidazol-2-yl)methanol;-   (4-Fluorodibenzo[b,d]furan-1-yl)(1H-imidazol-2-yl)methanol;-   (4-Fluoro-1-methyl-1H-indol-7-yl)(1H-imidazol-2-yl)methanol;-   (R)-(4-Fluoro-1-methyl-1H-indol-7-yl)(1H-imidazol-2-yl)methanol;-   (S)-(4-Fluoro-1-methyl-1H-indol-7-yl)(1H-imidazol-2-yl)methanol;-   (1-Ethyl-4-fluoro-1H-indol-7-yl)(1H-imidazol-2-yl)methanol;-   (2,3-Dihydro-1H-pyrrolo[1,2-a]indol-5-yl)(1H-imidazol-2-yl)methanol;-   (4-Fluoro-8-methylnaphthalen-1-yl)(1H-imidazol-2-yl)methanol;-   (1-Ethyl-5-fluoro-indolizin-8-yl)-(1H-imidazol-2-yl)methanol;-   (3-Chloro-8-fluoro-indolizin-5-yl)-(1H-imidazol-2-yl)methanol;-   (4-Fluoro-1-methyl-1H-indazol-7-yl)(1H-imidazol-2-yl)methanol;-   (3-Ethyl-7-fluorobenzofuran-4-yl)(1H-1,2,4-triazol-5-yl)methanol;-   (4-Fluoro-2-(pyrrolidin-1-yl)phenyl)(1H-1,2,4-triazol-5-yl)methanol;-   (4-Fluoro-2-(thiazol-2-yl)phenyl)(1H-imidazol-2-yl)methanol;-   [7-Fluoro-3-(1-methylcyclopropyl)benzofuran-4-yl]-(1H-imidazol-2-yl)methanol;    or a pharmaceutically acceptable salt thereof.

In another aspect, the present application provides a compound thatbinds to an allosteric site of a PAR2 polypeptide comprising an aminoacid sequence set forth in SEQ ID NO.: 1, wherein the compound interactswith one or more amino acid residues selected from the group consistingof Asp 228, Lys 131, His 135, and Tyr 82 of SEQ ID NO.: 1. In someembodiments, the compound binds to an allosteric site of a PAR2polypeptide comprising an amino acid sequence set forth in SEQ ID NO.:1, wherein the compound interacts with amino acid residues Asp 228, Lys131, and His 135 of SEQ ID NO.: 1. In some embodiments, the compoundbinds to an allosteric site of a PAR2 polypeptide comprising an aminoacid sequence set forth in SEQ ID NO.: 1, wherein the compound interactswith amino acid residues Asp 228, Lys 131, His 135, and Tyr 82 of SEQ IDNO.: 1. In some embodiments, such a compound is an antagonist of PAR2.In some embodiments, such a compound is a small molecule (e.g., a smallmolecule antagonist). In certain embodiments of the forgoing, thecompound has a structure of formula (I), (I-A), or (I-B), or apharmaceutically acceptable salt thereof.

Compounds which act on their target with long mean target residencetimes have been shown to have potential advantages such as long durationof activity and target selectivity. This can be measured on enzymes andproteins using methods such as surface plasmon resonance spectroscopy,radiochemical binding assays or inferred from time-dependent studies ina biochemical assay. The kinetic methods can be used to determine theon-rate (K_(on)), the off-rate (K_(off)) and the K_(d) value for a givencompound (Copeland et al, Nat. Rev. Drug Disc. 2006, 5, 730-739). Thesekinetic measurements can either be reported as residence time(τ=1/k_(off)), or as the dissociative half life (t_(1/2)=0.693/k_(off)).The value of the residence time or dissociative half-life needed toobtain a long duration of activity (e.g. PD effect) is thought to varyfrom one target to another and is generally influenced by thesurrounding environmental factors such as local concentrations ofcompeting ligands (such as agonists), protein turnover rate as well asthe distribution and localization of the compound. Compounds with thisproperty are also sometimes described as having slow off-rate kinetics.

In another aspect, the present application provides a compound thatbinds to an allosteric site of PAR2 polypeptide comprising an amino acidsequence set forth in SEQ ID NO.: 1, wherein said compound has a targetdissociative half life (t_(1/2)) of greater than 10 minutes. In someembodiments, the present application provides a compound that binds toan allosteric site of PAR2 polypeptide comprising an amino acid sequenceset forth in SEQ ID NO.: 1, wherein said compound has a targetdissociative half life (t_(1/2)) selected from over 3000 minutes, 10 to3000 minutes, 10 to 2000 minutes, 10 to 1000 minutes, 10 to 900 minutes,10 to 800 minutes, 10 to 700 minutes, 10 to 600 minutes, 10 to 500minutes, 10 to 400 minutes, 10 to 300 minutes, 10 to 200 minutes, 10 to100 minutes, 10 to 50 minutes, 10 to 40 minutes, 10 to 30 minutes, and10 to 20 minutes. In some embodiments, such a compound has a targetdissociative half life of 10 to 200 minutes. In some embodiments of theforgoing, the compound binds to an allosteric site of a PAR2 polypeptidecomprising an amino acid sequence set forth in SEQ ID NO.: 1, whereinthe compound interacts with one or more amino acid residues selectedfrom the group consisting of Asp 228, Lys 131, His 135, and Tyr 82 ofSEQ ID NO.: 1. In some embodiments, the compound interacts with aminoacid residues Asp 228, Lys 131, and His 135 of SEQ ID NO.: 1. In someembodiments, the compound interacts with amino acid residues Asp 228,Lys 131, His 135, and Tyr 82 of SEQ ID NO.: 1. In certain embodiments,the dissociative half life is determined in either a FLPR dissociationassay, surface plasmon resonance assay or radiochemical binding assay.In some embodiments, such a compound is an antagonist of PAR2. In someembodiments, such a compound is a small molecule (e.g., a small moleculeantagonist). In some embodiments of the forgoing, the compound has astructure of formula (I), (I-A), or (I-B), or a pharmaceuticallyacceptable salt thereof.

In certain embodiments, this application relates to a pharmaceuticalcomposition comprising (a) a compound described herein, or apharmaceutically acceptable salt thereof; and (b) a pharmaceuticallyacceptable excipient.

In certain embodiments, this application relates to a compound describedherein, or a pharmaceutically acceptable salt thereof, or apharmaceutical composition comprising any one of the foregoing, for useas a medicament.

In certain embodiments, this application relates to a method of treatinga disease or disorder mediated by PAR2 activity, comprisingadministering to a subject in need of such treatment an effective amountof at least one compound described herein, or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition comprising anyone of the foregoing. In certain such embodiments, the disease ordisorder mediated by PAR2 activity is selected from the group consistingof pain, musculoskeletal inflammation (such as osteoarthritis),neuroinflammatory disorders, airway inflammation, itch, dermatitis, orcolitis. In certain such embodiments, the disease or disorder mediatedby PAR2 activity is osteoarthritis.

In certain embodiments, this application relates to the use of acompound described herein, or a pharmaceutically acceptable saltthereof, or a pharmaceutical composition of any one of the foregoing, inthe preparation of a medicament for the treatment of diseases ordisorders regulated by PAR2 activity, and the use of such compounds fortreatment of such diseases and disorders. In certain such embodiments,the disease or disorder is selected from the group consisting of pain,musculoskeletal inflammation (such as osteoarthritis), neuroinflammatorydisorders, airway inflammation, itch, dermatitis, or colitis. In certainsuch embodiments, the disease or disorder mediated by PAR2 activity isosteoarthritis.

In certain embodiments, this application relates to a method ofmodulating (e.g., inhibiting) the activity of a PAR2 receptor,comprising contacting a cell comprising the PAR2 with an effectiveamount of at least one compound described herein, or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition of any one ofthe foregoing. In certain such embodiments, the contacting is in vitro,ex vivo, or in vivo.

In certain embodiments, this application relates to a method of treatinga disease or disorder in a patient in need thereof, comprisingadministering a compound described herein, or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition of any one ofthe foregoing, wherein the disease or disorder is selected from thegroup consisting of pain, musculoskeletal inflammation (such asosteoarthritis), neuroinflammatory disorders, airway inflammation, itch,dermatitis, or colitis. In certain such embodiments, the disease ordisorder mediated by PAR2 activity is osteoarthritis.

Those skilled in the art will recognize that the species listed orillustrated herein are not exhaustive, and that additional specieswithin the scope of these defined terms may also be selected.

The application also includes pharmaceutically acceptable prodrugs,salts, solvates, such as hydrates, of the compounds described herein,preferably of those described above and of the specific compoundsexemplified herein, and pharmaceutical compositions comprising suchprodrugs, salts, or solvates, such as hydrates, and methods of usingsuch salts or hydrates.

The present application also relates to pharmaceutically activemetabolites of compounds described herein, and uses of such metabolitesin the methods of the application.

Definitions

The definitions set forth in this application are intended to clarifyterms used throughout this application.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art to which this application belongs. All patents, applications,published applications and other publications referred to herein areincorporated by reference in their entireties to disclose and describethe methods and/or materials in connection with which the publicationsare cited. If a definition set forth in this section is contrary to orotherwise inconsistent with a definition set forth in a patent,application, or other publication that is herein incorporated byreference, the definition set forth in this section prevails over thedefinition incorporated herein by reference. Although any methods andmaterials similar or equivalent to those described herein can also beused in the practice or testing of the embodiments in the presentapplication, the preferred methods and materials are now described.

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about.” It isunderstood that, whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation to such given valuethat would reasonably be inferred based on the ordinary skill in theart, including equivalents and approximations due to the experimentaland/or measurement conditions for such given value. Whenever a yield isgiven as a percentage, such yield refers to a mass of the entity forwhich the yield is given with respect to the maximum amount of the sameentity that could be obtained under the particular stoichiometricconditions. Concentrations that are given as percentages refer to massratios, unless indicated differently.

Except as otherwise noted, the methods and techniques of the presentembodiments are generally performed according to conventional methodswell known in the art and as described in various general and morespecific references that are cited and discussed throughout the presentspecification. See, e.g., Loudon, Organic Chemistry, Fourth Edition, NewYork: Oxford University Press, 2002, pp. 360-361, 1084-1085; Smith andMarch, March's Advanced Organic Chemistry: Reactions, Mechanisms, andStructure, Fifth Edition, Wiley-Interscience, 2001.

The nomenclature used herein to name the subject compounds isillustrated in the Examples herein. This nomenclature has generally beenderived using the commercially-available ChemBioDraw Ultra software(Cambridgesoft/Perkin Elmer), Version 12.0.

It is to be understood that the present description is not limited toparticular embodiments described, as such may, of course, vary. It isalso to be understood that the terminology used herein is for thepurpose of describing particular embodiments only, and is not intendedto be limiting, since the scope of the present application will belimited only by the appended claims.

It is appreciated that certain features of the application, which are,for clarity, described in the context of separate embodiments, may alsobe provided in combination in a single embodiment. Conversely, variousfeatures of the application, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination. All combinations of the embodimentspertaining to the chemical groups represented by the variables arespecifically embraced by the present application and are disclosedherein just as if each and every combination was individually andexplicitly disclosed, to the extent that such combinations embracecompounds that are stable compounds (i.e., compounds that can beisolated, characterized, and tested for biological activity). Inaddition, all subcombinations of the chemical groups listed in theembodiments describing such variables are also specifically embraced bythe present application and are disclosed herein just as if each andevery such sub-combination of chemical groups was individually andexplicitly disclosed herein.

Any formula depicted herein is intended to represent a compound of thatstructural formula as well as certain variations or forms. E.g., aformula given herein is intended to include a racemic form, or one ormore enantiomeric, diastereomeric, or geometric isomers, or tautomericforms, or a mixture thereof. Additionally, any formula given herein isintended to refer also to a solvate, such as a hydrate, solvate, orpolymorph of such a compound, or a mixture thereof. Any formula givenherein is intended to refer to amorphous and/or crystalline physicalforms of the compound. The compounds described herein may beanalytically pure, or a mixture in which the compound comprises at least50%, at least 70%, at least 80%, at least 90%, at least 95%, or at least98% by weight of the mixture.

In addition, where features or aspects of the embodiments of thisapplication are described in terms of Markush groups, those skilled inthe art will recognize that embodiments described herein is also therebydescribed in terms of any individual member or subgroup of members ofthe Markush group. E.g., if X is described as selected from the groupconsisting of bromine, chlorine, and iodine, claims for X being bromineand claims for X being bromine and chlorine are fully described.

The term “herein” refers to the entire application.

As used herein, the singular forms “a,” “an,” and “the” include pluralreferents unless the context clearly dictates otherwise. It is furthernoted that the claims may be drafted to exclude any optional element. Assuch, this statement is intended to serve as antecedent basis for use ofsuch exclusive terminology as “solely,” “only” and the like inconnection with the recitation of claim elements, or use of a “negative”limitation.

As used herein, the terms “including,” “containing,” and “comprising”are used in their open, non-limiting sense.

As used herein, “subject” (as in the subject of the treatment) refers toboth mammals and non-mammals. Mammals include, e.g., humans; non-humanprimates, e.g. apes and monkeys; and non-primates, e.g. mice, rats,rabbits, dogs, cats, cattle, horses, sheep, and goats. Non-mammalsinclude, e.g., worms, fish and birds. In some embodiments, the subjectis a human.

“Substantially” as the term is used herein refers to being completely oralmost completely; e.g., a composition that is “substantially free” of acomponent either has none of the component or contains such a traceamount that any relevant functional property of the composition isunaffected by the presence of the trace amount, or a compound is“substantially pure” is there are only negligible traces of impuritiespresent.

The term “acyl” is art-recognized and refers to a group represented bythe general formula hydrocarbylC(O)—, preferably alkylC(O)—.

The term “acylamino” is art-recognized and refers to an amino groupsubstituted with an acyl group and may be represented, e.g., by theformula hydrocarbylC(O)NH—.

The term “acyloxy” is art-recognized and refers to a group representedby the general formula hydrocarbylC(O)O—, preferably alkylC(O)O—.

The term “alkoxy” refers to an alkyl group, preferably a lower alkylgroup, having an oxygen attached thereto. Representative alkoxy groupsinclude methoxy, ethoxy, propoxy, tert-butoxy and the like.

The term “alkoxyalkyl” refers to an alkyl group substituted with analkoxy group and may be represented by the general formulaalkyl-O-alkyl.

The term “alkenyl”, as used herein, refers to an aliphatic groupcontaining at least one double bond and is intended to include both“unsubstituted alkenyls” and “substituted alkenyls”, the latter of whichrefers to alkenyl moieties having substituents replacing a hydrogen onone or more carbons of the alkenyl group. Such substituents may occur onone or more carbons that are included or not included in one or moredouble bonds. Moreover, such substituents include all those contemplatedfor alkyl groups, as discussed below, except where stability isprohibitive. E.g., substitution of alkenyl groups by one or more alkyl,carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.

The term “alkynyl”, as used herein, refers to an aliphatic groupcontaining at least one triple bond and is intended to include both“unsubstituted alkynyls” and “substituted alkynyls”, the latter of whichrefers to alkynyl moieties having substituents replacing one or morehydrogens on one or more carbons of the alkynyl group. Such substituentsmay occur on one or more carbons that are included or not included inone or more triple bonds. Moreover, such substituents include all thosecontemplated for alkyl groups, as discussed above, except wherestability is prohibitive. E.g., substitution of alkynyl groups by one ormore alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups iscontemplated.

An “alkyl” group or “alkane” is a straight chained or branchednon-aromatic hydrocarbon which is completely saturated. Typically, astraight chained or branched alkyl group has from 1 to about 20 carbonatoms, such as from 1 to 12 carbon atoms, preferably from 1 to about 10,more preferably from 1 to 4, unless otherwise defined. Examples ofstraight chained and branched alkyl groups include methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl,isopentyl, tert-pentyl, hexyl, isohexyl, pentyl and octyl. A C₁-C₆straight chained or branched alkyl group is also referred to as a “loweralkyl” group.

Moreover, the term “alkyl” (or “lower alkyl”) as used throughout thespecification, examples, and claims is intended to include both“unsubstituted alkyls” and “substituted alkyls”, the latter of whichrefers to alkyl moieties having substituents replacing a hydrogen ormore hydrogens on one or more carbons of the hydrocarbon backbone. Suchsubstituents, if not otherwise specified, can include, e.g., a halogen,a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl,or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or athioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, aphosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro,an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, asulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or anaromatic or heteroaromatic moiety. It will be understood by thoseskilled in the art that the moieties substituted on the hydrocarbonchain can themselves be substituted, if appropriate. For instance, thesubstituents of a substituted alkyl may include substituted andunsubstituted forms of amino, azido, imino, amido, phosphoryl (includingphosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido,sulfamoyl and sulfonate), and silyl groups, as well as ethers,alkylthios, carbonyls (including ketones, aldehydes, carboxylates, andesters), —CF₃, —CN and the like. Exemplary substituted alkyls aredescribed below. Cycloalkyls can be further substituted with alkyls,alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl-substituted alkyls,—CF₃, —CN, and the like.

The term “(ATOM)_(i-j)” with j>i, when used in conjunction with achemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, oralkoxy is meant to include groups that contain from i to j (including iand j) atoms. E.g., the term “C_(x-y)alkyl” refers to substituted orunsubstituted saturated hydrocarbon groups, including straight-chainalkyl and branched-chain alkyl groups that contain from x to y carbonsin the chain, including haloalkyl groups such as trifluoromethyl and2,2,2-trifluoroethyl, etc. C₀ alkyl refers to a hydrogen atom where thegroup is in a terminal position, a bond if internal. Similarly, e.g.,C₃₋₆cycloalkyl refers to a cycloalkyl as defined herein that has 3 to 6carbon ring atoms. The terms “C_(2-y)alkenyl” and “C_(2-y)alkynyl” referto substituted or unsubstituted unsaturated aliphatic groups analogousin length and possible substitution to the alkyls described above, butthat contain at least one double or triple bond respectively.

The term “alkylamino”, as used herein, refers to an amino groupsubstituted with at least one alkyl group.

The term “alkylthio”, as used herein, refers to a thiol groupsubstituted with an alkyl group and may be represented by the generalformula alkylS-.

The term “hydrocarbyl”, as used herein, refers to a group that is bondedthrough a carbon atom that does not have a ═O or ═S substituent, andtypically has at least one carbon-hydrogen bond and a primarily carbonbackbone, but may optionally include heteroatoms. Thus, groups likemethyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered to behydrocarbyl for the purposes of this application, but substituents suchas acetyl (which has a ═O substituent on the linking carbon) and ethoxy(which is linked through oxygen, not carbon) are not. Hydrocarbyl groupsinclude, but are not limited to aryl, heteroaryl, carbocycle,heterocyclyl, alkyl, alkenyl, alkynyl, and combinations thereof.

The terms “amine” and “amino” are art-recognized and refer to bothunsubstituted and substituted amines and salts thereof, e.g., a moietythat can be represented by

wherein each R³⁰ independently represents a hydrogen or a hydrocarbylgroup, or two R³⁰ are taken together with the N atom to which they areattached complete a heterocycle having from 4 to 8 atoms in the ringstructure.

The term “aminoalkyl”, as used herein, refers to an alkyl groupsubstituted with an amino group.

The term “amide”, as used herein, refers to a group:

wherein each R³⁰ independently represent a hydrogen or hydrocarbylgroup, or two R³⁰ are taken together with the N atom to which they areattached complete a heterocycle having from 4 to 8 atoms in the ringstructure.

The term “carbamate” is art-recognized and refers to a group

wherein R²⁹ and R³⁰ independently represent hydrogen or a hydrocarbylgroup, such as an alkyl group, or R²⁹ and R³⁰ taken together with theintervening atom(s) complete a heterocycle having from 4 to 8 atoms inthe ring structure.

The term “halogen,” or “halide” represents chlorine, fluorine, bromine,or iodine. The term “halo” represents fluoro, chloro, bromo, or iodo.

The term “haloalkyl”, as used herein, refers to an alkyl group with oneor more halo substituents, or one, two, or three halo substituents.Examples of haloalkyl groups include —CF₃, —CH₂F, —CHF₂, —CH₂Br,—CH₂CF₃, and —CH₂CH₂F.

The term “heteroatom”, as used herein, refers to an atom of any elementother than carbon or hydrogen. Exemplary heteroatoms include but are notlimited to nitrogen, oxygen, and sulfur.

The term “heteroalkyl”, as used herein, refers to a saturated orunsaturated chain of carbon atoms and at least one heteroatom, whereinno two heteroatoms are adjacent.

The term “aryl”, as used herein, includes substituted or unsubstitutedmonocyclic aromatic rings in which each atom of the ring is carbon.Preferably the ring is a 5- to 7-membered ring, more preferably a6-membered ring. The term “aryl” also includes polycyclic ring systemshaving two or more cyclic rings in which two or more carbons are commonto two adjoining rings wherein at least one of the rings is aromatic,e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls,cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Aryl groupsinclude benzene, naphthalene, phenanthrene, phenol, aniline, and thelike.

The term “aralkyl”, as used herein, refers to an alkyl group substitutedwith an aryl group.

An “aroyl” group, as the term is used herein, refers to an aryl groupbonded via an exocyclic carbonyl group, such as a benzoyl group.

The term “heteroaryl”, as used herein, includes substituted orunsubstituted monocyclic aromatic ring system, preferably 5- to7-membered aromatic rings, more preferably 5- to 6-membered rings, whosering structures include at least one heteroatom, preferably one to fourheteroatoms, more preferably one to two heteroatoms. E.g., a 5-memberedheteroaryl is furan, thiophene, pyrrole, oxazole, isoxazole, thiazole,isothiazole, pyrazole, imidazole, oxadiazole, thiadiazole, triazole, ortetrazole. In another example, a 6-membered heteroaryl is pyridine,pyrazine, pyrimidine, pyridazine, or triazine. The term “heteroaryl”also include substituted or unsubstituted “polycyclic” ring systemshaving two or more cyclic rings in which two or more carbons are commonto two adjoining rings wherein at least one of the rings isheteroaromatic, e.g., the other cyclic rings can be cycloalkyls,cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.

Illustrative examples of heteroaryl groups include but are not limitedto the following entities, in the form of properly bonded moieties:

The term “heteroaralkyl” or “hetaralkyl”, as used herein, refers to analkyl group substituted with a heteroaryl group.

A “heteroaroyl” group, as the term is used herein, refers to aheteroaryl group bonded via an exocyclic carbonyl group, analogous to abenzoyl group but wherein the phenyl ring of the benzoyl group isreplaced by a heteroaryl group.

The terms “heterocyclyl”, “heterocycle”, and “heterocyclic”, as usedherein, refer to substituted or unsubstituted non-aromatic ringstructures, preferably 3- to 10-membered rings, more preferably 3- to7-membered rings, whose ring structures include at least one heteroatom,preferably one to four heteroatoms, more preferably one or twoheteroatoms. The terms “heterocyclyl” and “heterocyclic” also includesubstituted or unsubstituted polycyclic ring systems having two or morecyclic rings in which two or more carbons are common to two adjoiningrings wherein at least one of the rings is heterocyclic, e.g., the othercyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls,heteroaryls, and/or heterocyclyls. Heterocyclyl groups include, e.g.,piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, andthe like, such as e.g., piperidine, piperazine, pyrrolidine, morpholine,lactones, lactams, azetidines, and the like.

The term “heterocyclylalkyl”, as used herein, refers to an alkyl groupsubstituted with a heterocycle group which is optionally substituted.

The terms “carbocycle”, and “carbocyclic”, as used herein, refers to asaturated or unsaturated ring in which each atom of the ring is carbon.The term carbocycle includes both aromatic carbocycles and non-aromaticcarbocycles. Non-aromatic carbocycles include both cycloalkane rings, inwhich all carbon atoms are saturated, and cycloalkene rings, whichcontain at least one double bond. “Carbocycle” includes 5-7 memberedmonocyclic and 8-12 membered bicyclic rings. Each ring of a bicycliccarbocycle may be selected from saturated, unsaturated and aromaticrings. Carbocycle includes bicyclic molecules in which one, two or threeor more atoms are shared between the two rings. The term “fusedcarbocycle” refers to a bicyclic carbocycle in which each of the ringsshares two adjacent atoms with the other ring. Each ring of a fusedcarbocycle may be selected from saturated, unsaturated and aromaticrings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, maybe fused to a saturated or unsaturated ring, e.g., cyclohexane,cyclopentane, or cyclohexene. Any combination of saturated, unsaturatedand aromatic bicyclic rings, as valence permits, is included in thedefinition of carbocyclic. Exemplary “carbocycles” include cyclopentane,cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene,1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene andadamantane. Exemplary fused carbocycles include decalin, naphthalene,1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane,4,5,6,7-tetrahydro-1H-indene and bicyclo[4.1.0]hept-3-ene. “Carbocycles”may be substituted at any one or more positions capable of bearing ahydrogen atom.

A “cycloalkyl” group, as used herein, refers to a substituted orunsubstituted cyclic hydrocarbon which is completely saturated.“Cycloalkyl” includes substituted or unsubstituted monocyclic andbicyclic rings. Typically, a monocyclic cycloalkyl group has from 3 toabout 10 carbon atoms, more typically 3 to 8 carbon atoms unlessotherwise defined. Such a monocyclic cycloalkyl group may be substitutedor unsubstituted. The second ring of a bicyclic cycloalkyl may beselected from saturated, unsaturated and aromatic rings that aresubstituted or unsubstituted. Cycloalkyl includes substituted orunsubstituted bicyclic molecules in which one, two or three or moreatoms are shared between the two rings. The term “fused cycloalkyl”refers to a substituted or unsubstituted bicyclic cycloalkyl in whicheach of the rings shares two adjacent atoms with the other ring. Thesecond ring of a fused bicyclic cycloalkyl may be selected fromsaturated, unsaturated and aromatic rings.

The term “carbocyclylalkyl”, as used herein, refers to an alkyl groupsubstituted with a carbocycle group.

A “cycloalkenyl” group, as used herein, refers to a cyclic hydrocarboncontaining one or more double bonds. A “cycloalkynyl” group is a cyclichydrocarbon containing one or more triple bonds.

The terms “polycyclyl”, “polycycle”, and “polycyclic”, as used herein,refer to two or more rings (e.g., cycloalkyls, cycloalkenyls,cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls) in which two ormore atoms are common to two adjoining rings, e.g., the rings are “fusedrings”. Each of the rings of the polycycle can be substituted orunsubstituted. In certain embodiments, each ring of the polycyclecontains from 3 to 10 atoms in the ring, preferably from 5 to 7.

The term “carbonate” is art-recognized and refers to a group —OCO₂—R³⁰,wherein R³⁰ represents a hydrocarbyl group.

The term “carboxy”, as used herein, refers to a group represented by theformula —CO₂H.

The term “ester”, as used herein, refers to a group —C(O)OR³⁰ whereinR³⁰ represents a hydrocarbyl group.

The term “ether,” as used herein, refers to a hydrocarbyl group linkedthrough an oxygen to another hydrocarbyl group. Accordingly, an ethersubstituent of a hydrocarbyl group may be hydrocarbyl-O—. Ethers may beeither symmetrical or unsymmetrical. Examples of ethers include, but arenot limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethersinclude “alkoxyalkyl” groups, which may be represented by the generalformula alkyl-O-alkyl.

The term “sulfate” is art-recognized and refers to the group —OSO₃H, ora pharmaceutically acceptable salt thereof.

The term “sulfonamide” is art-recognized and refers to the grouprepresented by the general formulae

wherein R²⁹ and R³⁰ independently represents hydrogen or hydrocarbyl,such as alkyl, or R²⁹ and R³⁰ taken together with the interveningatom(s) complete a heterocycle having from 4 to 8 atoms in the ringstructure.

The term “sulfoxide” is art-recognized and refers to the group—S(O)—R³⁰, wherein R³⁰ represents a hydrocarbyl.

The term “sulfonate” is art-recognized and refers to the group SO₃H, ora pharmaceutically acceptable salt thereof.

The term “sulfone” is art-recognized and refers to the group —S(O)₂—R³⁰,wherein R³⁰ represents a hydrocarbyl.

The term “thioalkyl”, as used herein, refers to an alkyl groupsubstituted with a thiol group.

The term “thioester”, as used herein, refers to a group —C(O)SR³⁰ or—SC(O)R³⁰ wherein R³⁰ represents a hydrocarbyl.

The term “thioether”, as used herein, is equivalent to an ether, whereinthe oxygen is replaced with a sulfur.

The term “urea” is art-recognized and may be represented by the generalformula

wherein R²⁹ and R³⁰ independently represent hydrogen or a hydrocarbyl,such as alkyl, or either occurrence of R²⁹ taken together with R³⁰ andthe intervening atom(s) complete a heterocycle having from 4 to 8 atomsin the ring structure.

The term “substituted”, as used herein, refers to moieties havingsubstituents replacing one or more hydrogens on one or more carbons ofthe backbone. It will be understood that “substitution” or “substitutedwith” includes the implicit proviso that such substitution is inaccordance with permitted valence of the substituted atom and thesubstituent, and that the substitution results in a stable compound,e.g., which does not spontaneously undergo transformation such as byrearrangement, cyclization, elimination, etc. As used herein, the term“substituted” is contemplated to include all permissible substituents oforganic compounds. In a broad aspect, the permissible substituentsinclude acyclic and cyclic, branched and unbranched, carbocyclic andheterocyclic, aromatic and non-aromatic substituents of organiccompounds. The permissible substituents can be one or more and the sameor different for appropriate organic compounds. For purposes of thisapplication, the heteroatoms such as nitrogen may have hydrogensubstituents and/or any permissible substituents of organic compoundsdescribed herein which satisfy the valences of the heteroatoms. In someembodiments, “substituted” means that the specified group or moietybears one, two, or three substituents. In other embodiments,“substituted” means that the specified group or moiety bears one or twosubstituents. In still other embodiments, “substituted” refers to thespecified group or moiety bears one substituent.

Substituents can include any substituents described herein, e.g., alower alkyl (such as C₁₋₆ alkyl, e.g., -methyl, -ethyl, and -propyl), ahalogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl,a formyl, or an acyl), a thiocarbonyl (such as a thioester, athioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, aphosphonate, a phosphinate, an amino, an amido, an amidine, an imine, acyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, asulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, anaralkyl, or an aromatic or heteroaromatic moiety. It will be understoodby those skilled in the art that substituents can themselves besubstituted, if appropriate.

Unless specifically stated as “unsubstituted,” references to chemicalmoieties herein are understood to include substituted variants. E.g.,reference to an “aryl” group or moiety implicitly includes bothsubstituted and unsubstituted variants. The term “unsubstituted” refersto that the specified group bears no substituents.

The term “optionally substituted”, as used herein, means thatsubstitution is optional and therefore it is possible for the designatedatom or moiety to be unsubstituted.

Any disubstituent referred to herein is meant to encompass the variousattachment possibilities when more than one of such possibilities areallowed. E.g., reference to disubstituent -A-B-, where A≠B, refersherein to such disubstituent with A attached to a first substitutedmember and B attached to a second substituted member, and it also refersto such disubstituent with A attached to the second substituted memberand B attached to the first substituted member.

“Protecting group”, as used herein, refers to a group of atoms that,when attached to a reactive functional group in a molecule, mask, reduceor prevent the reactivity of the functional group. Typically, aprotecting group may be selectively removed as desired during the courseof a synthesis. Examples of protecting groups can be found in Greene andWuts, Protective Groups in Organic Chemistry, 3^(rd) Ed., 1999, JohnWiley & Sons, NY and Harrison et al., Compendium of Synthetic OrganicMethods, Vols. 1-8, 1971-1996, John Wiley & Sons, NY. Representativenitrogen protecting groups include, but are not limited to, formyl,acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”),tert-butoxycarbonyl (“Boc”), trimethylsilyl (“TMS”),2-trimethylsilyl-ethanesulfonyl (“TES”), trityl and substituted tritylgroups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (“FMOC”),nitro-veratryloxycarbonyl (“NVOC”) and the like. Representativehydroxylprotecting groups include, but are not limited to, those wherethe hydroxyl group is either acylated (esterified) or alkylated such asbenzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranylethers, trialkylsilyl ethers (e.g., TMS or TIPS groups), glycol ethers,such as ethylene glycol and propylene glycol derivatives and allylethers.

The term “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

A “pharmaceutically acceptable salt” is intended to mean a salt of afree acid or base of a compound represented herein that is non-toxic,biologically tolerable, or otherwise biologically suitable foradministration to the subject. See, generally, S. M. Berge, et al.,“Pharmaceutical Salts,” J. Pharm. Sci., 1977, 66, 1-19. Preferredpharmaceutically acceptable salts are those that are pharmacologicallyeffective and suitable for contact with the tissues of subjects withoutundue toxicity, irritation, or allergic response. A compound describedherein may possess a sufficiently acidic group, a sufficiently basicgroup, both types of functional groups, or more than one of each type,and accordingly react with a number of inorganic or organic bases, andinorganic and organic acids, to form a pharmaceutically acceptable salt.

For a compound described herein that contains a basic group, such as anamine, a pharmaceutically acceptable salt may be prepared by anysuitable method available in the art, e.g., treatment of the free basewith an inorganic acid, such as hydrochloric acid, hydrobromic acid,sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid,and the like, or with an organic acid, such as acetic acid, phenylaceticacid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleicacid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid,fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid,salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidylacid, such as glucuronic acid or galacturonic acid, an alpha-hydroxyacid, such as mandelic acid, citric acid, or tartaric acid, an aminoacid, such as aspartic acid or glutamic acid, an aromatic acid, such asbenzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid, asulfonic acid, such as laurylsulfonic acid, p-toluenesulfonic acid,methanesulfonic acid, or ethanesulfonic acid, or any compatible mixtureof acids such as those given as examples herein, and any other acid andmixture thereof that are regarded as equivalents or acceptablesubstitutes in light of the ordinary level of skill in this technology.

For a compound described herein that contains an acidic group, such as acarboxylic acid group, base addition salts can be prepared by anysuitable method available in the art, e.g., treatment of such compoundwith a sufficient amount of the desired the desired base, either neat orin a suitable inert solvent. Examples of pharmaceutically acceptablebase addition salts include, but are not limited to, lithium, sodium,potassium, calcium, ammonium, zinc, or magnesium salt, or other metalsalts; organic amino salts, such as, alkyl, dialkyl, trialkyl, ortetra-alkyl ammonium salts.

Other examples of pharmaceutically acceptable salts include, but are notlimited to, camsylate, sulfates, pyrosulfates, bisulfates, sulfites,bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates,metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates,propionates, decanoates, caprylates, acrylates, formates, isobutyrates,caproates, heptanoates, propiolates, oxalates, malonates, succinates,suberates, sebacates, fumarates, maleates, butyne-1,4-dioates,hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates,dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates,sulfonates, methylsulfonates, propylsulfonates, besylates,xylenesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates,phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates,γ-hydroxybutyrates, glycolates, tartrates, and mandelates. Lists ofother suitable pharmaceutically acceptable salts are found inRemington's Pharmaceutical Sciences, 17^(th) Edition, Mack PublishingCompany, Easton, Pa., 1985.

The neutral forms of the compounds are preferably regenerated bycontacting the salt with a base or acid and isolating the parentcompound in the conventional manner. The parent form of the compounddiffers from the various salt forms in certain physical properties, suchas solubility in polar solvents, but otherwise the salts are equivalentto the parent form of the compound for the purposes of the presentapplication.

The term “prodrug” is intended to encompass compounds which, underphysiologic conditions, are converted into the therapeutically activeagents of the present application, e.g., a compound of described herein.A common method for making a prodrug is to include one or more selectedmoieties which are hydrolyzed under physiologic conditions to yield thedesired molecule. In certain embodiments, the prodrug is converted by anenzymatic activity of the host animal. E.g., a prodrug with a nitrogroup on an aromatic ring could be reduced by reductase to generate thedesired amino group of the corresponding active compound in vivo. Inanother example, functional groups such as a hydroxyl, carbonate, orcarboxylic acid in the parent compound are presented as an ester, whichcould be cleaved by esterases. Additionally, amine groups in the parentcompounds are presented in, but not limited to, carbamate, N-alkylatedor N-acylated forms (Simplício et al, “Prodrugs for Amines,” Molecules,(2008), 13:519-547). In certain embodiments, some or all of thecompounds described herein in a formulation represented above can bereplaced with the corresponding suitable prodrug.

A “pharmaceutically acceptable prodrug” is a prodrug that is non-toxic,biologically tolerable, and otherwise biologically suitable foradministration to the subject. Illustrative procedures for the selectionand preparation of suitable prodrug derivatives are described, e.g., in“Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

A “pharmaceutically active metabolite” or “metabolite” refers to apharmacologically active product of metabolism/biochemical modificationof a compound described herein, e.g., a compound of Formula (I), (I-A),(I-B), or salt thereof, under physiological conditions, e.g., throughcertain enzymatic pathway. E.g., an oxidative metabolite is formed byoxidation of the parent compound during metabolism, such as theoxidation of a pyridine ring to pyridine-N-oxide. In another example, anoxidative metabolite is formed by demethylation of a methoxy group toresult in a hydroxyl group.

Prodrugs and active metabolites of a compound may be determined usingroutine techniques known or available in the art. See, e.g., Bertoliniet al., J. Med. Chem. 1997, 40, 2011-2016; Shan et al., J. Pharm. Sci.1997, 86 (7), 765-767; Bagshawe, Drug Dev. Res. 1995, 34, 220-230;Bodor, Adv. Drug Res. 1984, 13, 255-331; Bundgaard, Design of Prodrugs(Elsevier Press, 1985); and Larsen, Design and Application of Prodrugs,Drug Design and Development (Krogsgaard-Larsen et al., eds., HarwoodAcademic Publishers, 1991).

Compounds of the present application, such as compounds of formulae (I),(I-A) and (I-B), can also exist as various “solvates” or “hydrates.” A“hydrate” is a compound that exists in a composition with watermolecules. The composition can include water in stoichiometricquantities, such as a monohydrate or a dihydrate, or can include waterin random amounts. A “solvate” is a similar composition except that asolvent other that water, such as with methanol, ethanol,dimethylformamide, diethyl ether and the like replaces the water. E.g.,methanol or ethanol can form an “alcoholate,”” which can again bestoichiometric or non-stoichiometric. Mixtures of such solvates orhydrates can also be prepared. The source of such solvate or hydrate canbe from the solvent of crystallization, inherent in the solvent ofpreparation or crystallization, or adventitious to such solvent.

The compounds of the application, including their pharmaceuticallyacceptable salts and prodrugs, can exist as various polymorphs,pseudo-polymorphs, or in amorphous state. The term “polymorph”, as usedherein, refers to different crystalline forms of the same compound andother solid state molecular forms including pseudo-polymorphs, such ashydrates, solvates, or salts of the same compound. Different crystallinepolymorphs have different crystal structures due to a different packingof molecules in the lattice, as a result of changes in temperature,pressure, or variations in the crystallization process. Polymorphsdiffer from each other in their physical properties, such as x-raydiffraction characteristics, stability, melting points, solubility, orrates of dissolution in certain solvents. Thus crystalline polymorphicforms are important aspects in the development of suitable dosage formsin pharmaceutical industry.

The present application further embraces isolated compounds according toformula (I), (I-A) or (I-B). The term “isolated compound” refers to apreparation of a compound of formula (I), (I-A) or (I-B), or a mixtureof compounds according to formula (I), (I-A) or (I-B), wherein theisolated compound has been separated from the reagents used, and/orbyproducts formed, in the synthesis of the compound or compounds.“Isolated” does not mean that the preparation is technically pure(homogeneous), but it is sufficiently pure to compound in a form inwhich it can be used therapeutically. Preferably an “isolated compound”refers to a preparation of a compound of formula (I), (I-A) or (I-B) ora mixture of compounds according to formula (I), (I-A) or (I-B), whichcontains the named compound or mixture of compounds according to formula(I), (I-A) or (I-B) in an amount of at least 10 percent by weight of thetotal weight. Preferably the preparation contains the named compound ormixture of compounds in an amount of at least 50% by weight of the totalweight; more preferably at least 80% by weight of the total weight; andmost preferably at least 90%, at least 95% or at least 98% by weight ofthe total weight of the preparation.

The compounds of the application and intermediates may be isolated fromtheir reaction mixtures and purified by standard techniques such asfiltration, liquid-liquid extraction, solid phase extraction,distillation, recrystallization or chromatography, including flashcolumn chromatography, or HPLC.

Isomerism and Tautomerism in Described Compounds

Tautomerism

Within the present application it is to be understood that a compounddescribed herein or a salt thereof may exhibit the phenomenon oftautomerism whereby two chemical compounds that are capable of facileinterconversion by exchanging a hydrogen atom between two atoms, toeither of which it forms a covalent bond. Since the tautomeric compoundsexist in mobile equilibrium with each other they may be regarded asdifferent isomeric forms of the same compound. It is to be understoodthat the formulae drawings within this specification can represent onlyone of the possible tautomeric forms. However, it is also to beunderstood that the application encompasses any tautomeric form, and isnot to be limited merely to any one tautomeric form utilized within theformulae drawings. The formulae drawings within this specification canrepresent only one of the possible tautomeric forms and it is to beunderstood that the specification encompasses all possible tautomericforms of the compounds drawn not just those forms which it has beenconvenient to show graphically herein. E.g., tautomerism may beexhibited by a pyrazolyl group bonded as indicated by the wavy line.While both substituents would be termed a 4-pyrazolyl group, it isevident that a different nitrogen atom bears the hydrogen atom in eachstructure.

Such tautomerism can also occur with substituted pyrazoles such as3-methyl, 5-methyl, or 3,5-dimethylpyrazoles, and the like. Anotherexample of tautomerism is amido-imido (lactam-lactim when cyclic)tautomerism, such as is seen in heterocyclic compounds bearing a ringoxygen atom adjacent to a ring nitrogen atom. E.g., the equilibrium:

is an example of tautomerism. Accordingly, a structure depicted hereinas one tautomer is intended to also include the other tautomer.Optical Isomerism

It will be understood that when compounds of the present applicationcontain one or more chiral centers, the compounds may exist in, and maybe isolated as pure enantiomeric or diastereomeric forms or as racemicmixtures. The present application therefore includes any possibleenantiomers, diastereomers, racemates in their pure forms or mixturesthereof, and salts thereof, of the compounds of the application.

The isomers resulting from the presence of a chiral center comprise apair of non-superimposable isomers that are called “enantiomers.” Singleenantiomers of a pure compound are optically active, i.e., they arecapable of rotating the plane of plane polarized light. Singleenantiomers are designated according to the Cahn-Ingold-Prelog system.The priority of substituents is ranked based on atomic weights, a higheratomic weight, as determined by the systematic procedure, having ahigher priority ranking. Once the priority ranking of the four groups isdetermined, the molecule is oriented so that the lowest ranking group ispointed away from the viewer. Then, if the descending rank order of theother groups proceeds clockwise, the molecule is designated (R) and ifthe descending rank of the other groups proceeds counterclockwise, themolecule is designated (S). In the example in Scheme 14, theCahn-Ingold-Prelog ranking is A>B>C>D. The lowest ranking atom, D isoriented away from the viewer.

In certain embodiments, the therapeutic preparation may be enriched toprovide predominantly one enantiomer of a compound (e.g., of formula(I), (I-A) or (I-B)). An enantiomerically enriched mixture may comprise,e.g., at least 60 mol percent of one enantiomer, or more preferably atleast 75, 90, 95, or even 99 mol percent. In certain embodiments, acompound of the application may have greater than 30% ee, 40% ee, 50%ee, 60% ee, 70% ee, 80% ee, 90% ee, or even 95% or greater ee. Incertain embodiments, the compound enriched in one enantiomer issubstantially free of the other enantiomer, wherein substantially freemeans that the substance in question makes up less than 10%, or lessthan 5%, or less than 4%, or less than 3%, or less than 2%, or less than1% as compared to the amount of the other enantiomer, e.g., in thecomposition or compound mixture. E.g., if a composition or compoundmixture contains 98 grams of a first enantiomer and 2 grams of a secondenantiomer, it would be said to contain 98 mol percent of the firstenantiomer and only 2% of the second enantiomer.

In certain embodiments, compounds of the application may have more thanone stereocenter. In certain such embodiments, compounds of theapplication may be enriched in one or more diastereomer. E.g., acompound of the application may have greater than 30% de, 40% de, 50%de, 60% de, 70% de, 80% de, 90% de, or even 95% or greater de.

Isolated optical isomers may be purified from racemic mixtures bywell-known chiral separation techniques, such as but not limited to,normal and reverse phase chromatography, and crystallization. Accordingto one such method, a racemic mixture of a compound of the application,or a chiral intermediate thereof, is separated using a chiral salt orcarried out on a Chiralcell OD column. The column is operated accordingto the manufacturer's instructions.

Isolated optical isomers (enantiomerically pure compounds) can also beprepared by the use of chiral intermediates or catalysts in synthesis.When a chiral synthetic intermediate is used, the optical center (chiralcenter) can be preserved without racemization throughout the remainderof the preparative procedure, as is well known in the art. Chiralcatalyst can be used to impart at least some degree of enantiomericpurity to products of reactions catalyzed by the chiral catalyst. And,in some cases, compounds having at least some degree of enantiomericenrichment can be obtained by physical processes such as selectivecrystallization of salts or complexes formed with chiral adjuvants.

A variety of compounds in the present application may exist inparticular geometric or stereoisomeric forms. The present applicationtakes into account all such compounds, including tautomers, cis- andtrans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers,(L)-isomers, the racemic mixtures thereof, and other mixtures thereof,as being covered within the scope of this application. All tautomericforms are encompassed in the present application. Additional asymmetriccarbon atoms may be present in a substituent such as an alkyl group. Allsuch isomers, as well as mixtures thereof, are intended to be includedin this application, unless the stereochemistry or isomeric form isspecifically indicated.

Rotational Isomerism

It is understood that due to chemical properties (i.e., resonancelending some double bond character to the C—N bond) of restrictedrotation about the amide bond linkage (as illustrated below) it ispossible to observe separate rotamer species and even, under somecircumstances, to isolate such species (see below). It is furtherunderstood that certain structural elements, including steric bulk orsubstituents on the amide nitrogen, may enhance the stability of arotamer to the extent that a compound may be isolated as, and existindefinitely, as a single stable rotamer. The present applicationtherefore includes any possible stable rotamers of formula (I) which arebiologically active in the treatment of cancer or other proliferativedisease states.

Regioisomerism

The preferred compounds of the present application have a particularspatial arrangement of substituents on the aromatic rings, which arerelated to the structure activity relationship demonstrated by thecompound class. Often such substitution arrangement is denoted by anumbering system; however, numbering systems are often not consistentbetween different ring systems. In six-membered aromatic systems, thespatial arrangements are specified by the common nomenclature “para” for1,4-substitution, “meta” for 1,3-substitution and “ortho” for1,2-substitution as shown below.

Isotopical Labeling in Described Compounds

The present application further includes all pharmaceutically acceptableisotopically labeled compound [e.g., of formula (I), (I-A) or (I-B)]. An“isotopically” or “radio-labeled” compound is a compound where one ormore atoms are replaced or substituted by an atom having an atomic massor mass number different from the atomic mass or mass number typicallyfound in nature (i.e., naturally occurring). E.g., in certainembodiments, in compounds [e.g., of formula (I), (I-A) or (I-B)],hydrogen atoms are replaced or substituted by one or more deuterium ortritium (e.g., hydrogen atoms on a C₁₋₆ alkyl or a C₁₋₆ alkoxy arereplaced with deuterium, such as d₃-methoxy or1,1,2,2-d₄-3-methylbutyl).

Certain isotopically labeled compounds [e.g., compounds of formula (I),(I-A) or (I-B)], e.g., those incorporating a radioactive isotope, areuseful in drug and/or substrate tissue distribution studies. Theradioactive isotopes tritium, i.e., ³H, and carbon 14, i.e., ¹⁴C, areparticularly useful for this purpose in view of their ease ofincorporation and ready means of detection.

Such isotopically labeled compounds are useful in metabolic studies(preferably with ¹⁴C), reaction kinetic studies (with, for example ²H or³H), detection or imaging techniques [such as positron emissiontomography (PET) or single-photon emission computed tomography (SPECT)]including drug or substrate tissue distribution assays, or inradioactive treatment of patients. Further, substitution with heavierisotopes such as deuterium (i.e., ²H) may afford certain therapeuticadvantages resulting from greater metabolic stability, for exampleincreased in vivo half-life or reduced dosage requirements.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O, and¹³N, can be useful in Positron Emission Tomography (PET) studies forexamining substrate receptor occupancy.

Isotopically labeled compounds [e.g., of formula (I), (I-A) or (I-B)] ortheir corresponding prodrugs can generally be prepared by conventionaltechniques known to those skilled in the art or by processes analogousto those described in the accompanying examples using an appropriateisotopically labeled reagent in place of the non-labeled reagentpreviously employed. Suitable isotopes that may be incorporated incompounds of the present application include but are not limited toisotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine,chlorine, and iodine, such as ²H (also written as D for deuterium), ³H(also written as T for tritium) ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O,¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵I, ¹³¹I, ³¹P, and³²P.

Isotopically labeled compounds of this application and prodrugs thereofcan generally be prepared by carrying out the procedures disclosed inthe schemes or in the examples and preparations described below bysubstituting a readily available isotopically labeled reagent for anon-isotopically labeled reagent.

Provisos may apply to any of the disclosed categories or embodimentssuch that specific embodiments or species may be excluded from suchcategories or embodiments.

In various embodiments, the compound or set of compounds, such as areused in the inventive methods, can be any one of any of the combinationsand/or sub-combinations of the above-listed embodiments.

Pharmaceutical Compositions

The compositions and methods of the present application may be utilizedto treat a subject, such as a mammal, e.g., human, or a non-humanmammal, in need thereof. When administered to an animal, such as ahuman, the composition or the compound is preferably administered as apharmaceutical composition comprising, e.g., a compound of theapplication and a pharmaceutically acceptable carrier. In certainembodiments, the application relates to a pharmaceutical compositioncomprising as active ingredient a therapeutically effective amount of acompound described herein, or a pharmaceutically acceptable salt,solvate, or prodrug thereof, in association with at least onepharmaceutically acceptable carrier, excipient, or diluent.

The term “pharmaceutically acceptable carrier”, as used herein, refersto a pharmaceutically acceptable material, composition or vehicle, suchas a liquid or solid filler, diluent, excipient, solvent orencapsulating material, which can act, e.g., to stabilize, increasesolubility or to increase the absorption of a compound such as acompound of the application. Each carrier must be “acceptable” in thesense of being compatible with the other ingredients of the formulationand not injurious to the patient.

Pharmaceutically acceptable carriers are well known in the art. E.g.,some examples of materials which can serve as pharmaceuticallyacceptable carriers include, but are not limited to: (1) sugars, such aslactose, glucose, sucrose or dextrans; (2) starches, such as corn starchand potato starch; (3) cellulose, and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4)powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients,such as cocoa butter and suppository waxes; (9) oils, such as peanutoil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; (10) glycols, such as glycerol or propylene glycol; (11)polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol;(12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14)buffering agents, such as magnesium hydroxide and aluminum hydroxide;(15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18)Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions;(21) antioxidants, such as ascorbic acid or glutathione; and (22) othernon-toxic compatible substances employed in pharmaceutical formulations,such as chelating agents, low molecular weight proteins or otherstabilizers or excipients.

The choice of a pharmaceutically acceptable carrier, including aphysiologically acceptable agent, depends, e.g., on the route ofadministration of the composition. The pharmaceutical composition can bea self-emulsifying or a self-microemulsifying drug delivery system. Thepharmaceutical composition also can be a liposome or other polymermatrix, which can have incorporated therein. Liposomes, e.g., whichcomprise phospholipids or other lipids, are nontoxic, physiologicallyacceptable and metabolizable carriers that are relatively simple to makeand administer.

Wetting agents, emulsifiers and lubricants, such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releaseagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the compositions.Such liquid compositions may optionally contain:pharmaceutically-acceptable excipients such as suspending agents (e.g.,sorbitol, methyl cellulose, sodium alginate, gelatin,hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel andthe like); non-aqueous vehicles, e.g., oil (e.g., almond oil orfractionated coconut oil), propylene glycol, ethyl alcohol, or water;preservatives (e.g., methyl or propyl p-hydroxybenzoate or sorbic acid);wetting agents such as lecithin; and, if desired, flavoring or coloringagents.

Examples of pharmaceutically acceptable antioxidants include: (1)water-soluble antioxidants, such as ascorbic acid, cysteinehydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfiteand the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate,butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT),lecithin, propyl gallate, alpha-tocopherol, and the like; and (3)metal-chelating agents, such as citric acid, ethylenediamine tetraaceticacid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

A pharmaceutical composition can be administered to a subject by any ofa number of routes of administration including, but not limited to,e.g., orally [e.g., drenches as in aqueous or non-aqueous solutions orsuspensions, tablets, pills, capsules (including sprinkle capsules andgelatin capsules), boluses, powders, granules, pastes for application tothe tongue]; absorption through the oral mucosa (e.g., sublingually);anally, rectally or vaginally (e.g., as a pessary, cream or foam);parenterally (including intramuscularly, intravenously, subcutaneouslyor intrathecally as, e.g., a sterile solution or suspension); nasally;intraperitoneally; subcutaneously; transdermally (for example as a patchapplied to the skin); and topically (e.g., as a cream, ointment or sprayapplied to the skin, or as an eye drop). The composition or compound mayalso be formulated for inhalation. In certain embodiments, thecomposition or compound may be simply dissolved or suspended in sterilewater. Details of appropriate routes of administration and compositionssuitable for same can be found in, e.g., U.S. Pat. Nos. 6,110,973,5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896, aswell as in patents cited therein. Sterile compositions are alsocontemplated by the application, including compositions that are inaccord with national and local regulations governing such compositions.Preferably, the compositions are formulated for intravenous or oraladministration.

For oral administration, the compounds of the application may beprovided in a solid form, such as a tablet, pills, dragees, powers,granules, or capsule, or as a solution, emulsion, or suspension. Toprepare the oral compositions, the active ingredient is mixed with oneor more pharmaceutically acceptable carriers, such as sodium citrate ordicalcium phosphate, and/or any of the following: (1) fillers orextenders, such as starches, lactose, sucrose, glucose, mannitol, and/orsilicic acid; (2) binders, such as, e.g., carboxymethylcellulose,alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3)humectants, such as glycerol; (4) disintegrating agents, such asagar-agar, calcium carbonate, potato or tapioca starch, alginic acid,certain silicates, and sodium carbonate; (5) solution retarding agents,such as paraffin; (6) absorption accelerators, such as quaternaryammonium compounds; (7) wetting agents, such as, e.g., cetyl alcohol andglycerol monostearate; (8) absorbents, such as kaolin and bentoniteclay; (9) lubricants, such a talc, calcium stearate, magnesium stearate,solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof;(10) complexing agents, such as, modified and unmodified cyclodextrins;(11) coloring agents; (12) emulsifying and suspending agents, such as,ethoxylated isostearyl alcohols, polyoxyethylene sorbitol, sorbitanesters, microcrystalline cellulose, aluminum metahydroxide, bentonite,agar, and tragacanth; and (13) other non-toxic compatible substancesemployed in pharmaceutical formulations, such as, without limitation,buffering agents, perfuming and preservative agents, sweetening agents,flavoring agents.

Oral tablets may be made by compression or molding, optionally with oneor more accessory ingredients, such as diluents, disintegrating agents,binding agents, lubricating agents, sweetening agents, flavoring agents,coloring agents and preservative agents. Suitable inert fillers includesodium and calcium carbonate, sodium and calcium phosphate, lactose,starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol,sorbitol, and the like. Exemplary liquid oral excipients includeethanol, glycerol, water, and the like. Starch, polyvinyl-pyrrolidone(PVP), sodium starch glycolate, microcrystalline cellulose, and alginicacid are exemplary disintegrating agents. Binding agents may includehydroxypropylmethyl cellulose, starch and gelatin. The lubricatingagent, if present, may be magnesium stearate, stearic acid, or talc. Ifdesired, the tablets may be coated with a material such as glycerylmonostearate or glyceryl distearate to delay absorption in thegastrointestinal tract, or may be coated with an enteric coating.

Other solid dosage forms of the pharmaceutical compositions, such asdragees, capsules (including sprinkle capsules and gelatin capsules),pills and granules, may optionally be scored or prepared with coatingsand shells, such as enteric coatings and other coatings well known inthe pharmaceutical-formulating art. E.g., to prepare hard gelatincapsules, active ingredient(s) may be mixed with a solid, semi-solid, orliquid diluent. Soft gelatin capsules may be prepared by mixing theactive ingredient with water, oil such as peanut oil or olive oil,liquid paraffin, a mixture of mono and di-glycerides of short chainfatty acids, polyethylene glycol 400, or propylene glycol.

The pharmaceutical compositions may also be formulated so as to provideslow or controlled release of the active ingredient therein using, e.g.,hydroxypropylmethyl cellulose in varying proportions to provide thedesired release profile, other polymer matrices, liposomes and/ormicrospheres. They may be sterilized by, e.g., filtration through abacteria-retaining filter, or by incorporating sterilizing agents in theform of sterile solid compositions that can be dissolved in sterilewater, or some other sterile injectable medium immediately before use.These compositions may also optionally contain opacifying agents and maybe of a composition that they release the active ingredient(s) only, orpreferentially, in a certain portion of the gastrointestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes. The activeingredient can also be in micro-encapsulated form, if appropriate, withone or more of the above-described excipients.

Liquid dosage forms useful for oral administration includepharmaceutically acceptable emulsions, lyophiles for reconstitution,microemulsions, solutions, suspensions, syrups and elixirs, or may belyophilized or presented as a dry product for reconstitution with wateror other suitable vehicle before use. In addition to the activeingredient, the liquid dosage forms may contain inert diluents commonlyused in the art, such as, e.g., water or other solvents, cyclodextrinsand derivatives thereof, solubilizing agents and emulsifiers, such asethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils(in particular, cottonseed, groundnut, corn, germ, olive, castor andsesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycolsand fatty acid esters of sorbitan, and mixtures thereof.

In addition, formulations of the pharmaceutical compositions foradministration to the mouth may be presented as a mouthwash, or an oralspray, or an oral ointment.

The phrases “parenteral administration” and “administered parenterally”,as used herein, means modes of administration other than enteral andtopical administration, usually by injection, and includes, withoutlimitation, intravenous, intramuscular, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intranasal,intrapeirtoneal, transtracheal, subcutaneous, subcuticular,intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternalinjection and infusion.

For parenteral use, the agents of the application may be provided insterile aqueous solutions or suspensions, buffered to an appropriate pHand isotonicity or in parenterally acceptable oil. Suitable aqueousvehicles include Ringer's solution and isotonic sodium chloride. Suchforms may be presented in unit-dose form such as ampoules or disposableinjection devices, in multi-dose forms such as vials from which theappropriate dose may be withdrawn, or in a solid form or pre-concentratethat can be reconstituted into a sterile injectable formulation, such assolutions or dispersions just prior to use, which may containantioxidants, buffers, bacteriostats, solutes which render theformulation isotonic with the blood of the intended recipient orsuspending or thickening agents. Illustrative infusion doses range fromabout 1 to 1000 μg/kg/minute of agent admixed with a pharmaceuticalcarrier over a period ranging from several minutes to several days.

Examples of suitable aqueous and nonaqueous carriers that may beemployed in the pharmaceutical compositions of the application includewater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol, and the like), and suitable mixtures thereof,vegetable oils, such as olive oil, and injectable organic esters, suchas ethyl oleate. Proper fluidity can be maintained, e.g., by the use ofcoating materials, such as lecithin, by the maintenance of the requiredparticle size in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms may be ensured by the inclusion of variousantibacterial and antifungal agents, e.g., paraben, chlorobutanol,phenol sorbic acid, and the like. It may also be desirable to includeisotonic agents, such as sugars, sodium chloride, and the like into thecompositions.

In some cases, in order to prolong the effect of a drug, it is desirableto slow the absorption of the drug from subcutaneous or intramuscularinjection. This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material having poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolution,which, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Injectable depot forms are made by forming microencapsulated matrices ofthe subject compounds in biodegradable polymers such aspolylactide-polyglycolide. Depending on the ratio of drug to polymer,and the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions that are compatible with body tissue.

In a preferred embodiment, when such pharmaceutical compositions are forhuman administration, particularly for invasive routes of administration(i.e., routes, such as injection or implantation, that circumventtransport or diffusion through an epithelial barrier), the aqueoussolution is pyrogen-free, or substantially pyrogen-free. The excipientscan be chosen, e.g., to effect delayed release of an agent or toselectively target one or more cells, tissues or organs.

For rectal, vaginal, or urethral administration, formulations of thepharmaceutical compositions may be presented as a suppository, which maybe prepared by mixing one or more active compounds with one or moresuitable nonirritating excipients or carriers comprising, e.g., cocoabutter, polyethylene glycol, a suppository wax or a salicylate, andwhich is solid at room temperature, but liquid at body temperature and,therefore, will melt in the rectum or vaginal cavity and release theactive compound. Formulations which are suitable for vaginaladministration also include pessaries, tampons, creams, gels, pastes,foams or spray formulations containing such carriers as are known in theart to be appropriate.

For topical applications or transdermal administration, the activecompounds of the present application may be mixed under sterileconditions with a pharmaceutically acceptable carrier, and with anypreservatives, buffers, excipients, or propellants, such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof. Dosage forms for the topicalinclude powders, sprays, ointments, pastes, creams, lotions, gels,solutions, patches and inhalants. The active compounds may be mixed witha pharmaceutical carrier at a concentration of about 0.1% to about 10%of drug to vehicle.

Powders and sprays can contain, in addition to an active compound,excipients such as lactose, talc, silicic acid, aluminum hydroxide,calcium silicates and polyamide powder, or mixtures of these substances.Sprays can additionally contain customary propellants, such aschlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, suchas butane and propane.

Transdermal patches have the added advantage of providing controlleddelivery of a compound of the present application to the body. Suchdosage forms can be made by dissolving or dispersing the active compoundin the proper medium. Absorption enhancers can also be used to increasethe flux of the compound across the skin. The rate of such flux can becontrolled by either providing a rate controlling membrane or dispersingthe compound in a polymer matrix or gel.

Ophthalmic formulations, eye ointments, powders, solutions and the like,are also contemplated as being within the scope of this application.Exemplary ophthalmic formulations are described in U.S. Publication Nos.2005/0080056, 2005/0059744, 2005/0031697 and 2005/004074 and U.S. Pat.No. 6,583,124, the contents of which are incorporated herein byreference. If desired, liquid ophthalmic formulations have propertiessimilar to that of lacrimal fluids, aqueous humor or vitreous humor orare compatible with such fluids. A preferred route of administration islocal administration (e.g., topical administration, such as eye drops,or administration via an implant).

Alternatively or additionally, compositions can be formulated fordelivery via a catheter, stent, wire, or other intraluminal device.Delivery via such devices may be especially useful for delivery to thebladder, urethra, ureter, rectum, or intestine.

Methods of introduction may also be provided by rechargeable orbiodegradable devices. Various slow release polymeric devices have beendeveloped and tested in vivo in recent years for the controlled deliveryof drugs, including proteinacious biopharmaceuticals. A variety ofbiocompatible polymers (including hydrogels), including bothbiodegradable and non-degradable polymers, can be used to form animplant for the sustained release of a compound at a particular targetsite.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the therapeutically effective amount of thepharmaceutical composition required. The term “therapeutically effectiveamount” or “dose”, or “dosage”, as used herein, refers to an amount ordose sufficient to generally bring about the desired therapeutic benefitor an amount sufficient to modulate the biological activity of thetarget receptor in subjects needing such treatment.

Effective amounts or dosages of the compounds of the application may beascertained by routine methods, such as modeling, dose escalation, orclinical trials, taking into account routine factors. Actual dosagelevels of the active ingredients in the pharmaceutical compositions maybe varied. In general, a suitable daily dose of an active compound usedin the compositions and methods of the application will be that amountof the compound that is the lowest dose effective to produce atherapeutic effect.

The selected dosage level will depend upon a variety of factorsincluding the activity of the particular compound or combination ofcompounds employed, or the salts, solvate, and prodrug thereof, theroute of administration, the time of administration, the rate ofexcretion of the particular compound(s) being employed, the duration ofthe treatment, other drugs, compounds and/or materials used incombination with particular compound(s) employed, age, sex, weight,condition, general health, prior medical history of the patient beingtreated, and the preference and experience of the physician orveterinarian in charge, and like factors well known in the medical arts.

E.g., in choosing a regimen for a subject, such as a patient, it canfrequently be necessary to begin with a higher dosage and when thecondition is under control to reduce the dosage. In another example, itis also possible to start at a dosage of the pharmaceutical compositionfor compound at levels lower than that required in order to achieve thedesired therapeutic effect and gradually increase the dosage until thedesired effect is achieved.

The compounds of the application are effective over a wide dosage range.E.g., in the treatment of adult humans, dosages from about 0.05 to about5000 mg, preferably from about 1 to about 2000 mg, and more preferablybetween about 2 and about 2000 mg per day can be used. A typical dosageis about 10 mg to about 1000 mg per day, or 25 to 200 mg per day, or 50to 100 mg per day, or less than 100 mg per day.

In some embodiments, the compounds of the application are dispensed inunit dosage form including from about 0.05 mg to about 1000 mg of activeingredient together with a pharmaceutically acceptable carrier per unitdosage. In other embodiments, a unit dosage form includes from about 10to about 200 mg of active ingredient. In other embodiments, dosage formssuitable for oral, nasal, pulmonal or transdermal administration includefrom about 125 μg to about 1250 mg, preferably from about 250 μg toabout 500 mg, and more preferably from about 2.5 mg to about 250 mg, ofthe compounds admixed with a pharmaceutically acceptable carrier ordiluent. Methods to determine efficacy and dosage are known to thoseskilled in the art (Isselbacher et al. (1996) Harrison's Principles ofInternal Medicine 13^(ed)., 1814-1882, herein incorporated byreference).

Dosage forms can be administered daily or more than once a day, such astwice or thrice daily. Alternatively dosage forms can be administeredless frequently than daily, such as every other day, or weekly, if foundto be advisable by a prescribing physician. A larger dosage can bedelivered by multiple administrations of the agent. In some embodiments,dosage forms are administered once, twice, or thrice daily. In preferredembodiments, the active compound will be administered once daily. Onceimprovement of the patient's disease has occurred, the dose may beadjusted for maintenance treatment. E.g., the dosage or the frequency ofadministration, or both, may be reduced as a function of the symptoms,to a level at which the desired therapeutic or prophylactic effect ismaintained. Of course, if symptoms have been alleviated to anappropriate level, treatment may cease. Patients may, however, requireintermittent treatment on a long-term basis upon any recurrence ofsymptoms. Patients may also require chronic treatment on a long-termbasis.

Methods and Uses

In various embodiments, compounds of the application can be used tomodulate, such as to activate (agonist), or to block activation of(antagonist), a PAR2 receptor. Accordingly, in various embodiments, theapplication provides a method of modulating a PAR2 receptor comprisingcontacting the receptor with an effective amount or concentration of acompound of the application. In various embodiments, the compound of theapplication is an antagonist of a PAR2 receptor. In various embodiments,contacting can take place in vivo within tissues of a patient, such as ahuman patient. In various embodiments, modulation of a PAR2 receptor,for example, antagonism of PAR2, by a compound of the application can beused to treat a disease or disorder in a patient, as described herein.

In various embodiments, the application provides a method of treating adisease or disorder in a patient wherein modulation of a PAR2 receptoris medically indicating, comprising administering to the subject, suchas a patient, a compound of the application in a dose, at a frequency,and for duration to provide a beneficial effect to the subject.Modulation, such as agonism or antagonism, of a PAR2 receptor can bemedically indicated in treatment of a disease or disorder wherein thePAR2 receptor plays a metabolic or regulatory role. Certain suchconditions can be treated by selective modulation of a PAR2 receptor,while the other protease-activated receptors such as PAR1, PAR3 and PAR4are not influenced by administration of the compound of the applicationat the dose provided. In various embodiments, compounds of theapplication can be PAR2 antagonists, and some of those are selectivePAR2 antagonists with respect to other protease-activated receptors suchas PAR1, PAR3 and PAR4. By “selective” is meant that one receptor ismodulated at concentrations of the compound at least 10 times lower thanthe concentrations at which the comparative receptor is modulated bythat compound. In further embodiments, the compound of the applicationcan further modulate other types or classes of protease-activatedreceptors such as PAR1, PAR3 and PAR4.

In various embodiments, the application provides a use of a compound ofthe application for treatment of a disease or disorder in a patient. Forexample, a compound of the application can be used in the preparation ofa medicament for administration to a patient suffering from a disease ordisorder. More specifically, the disease or disorder can comprise pain,musculoskeletal inflammation, neuroinflammatory disorders, airwayinflammation, itch, dermatitis, colitis and related conditions.

In some embodiments, the application provides a use of a compound of theapplication for treatment of a pain, including but not limited to acutepain, chronic pain, inflammatory and neuropathic pain. The pain may bechronic, allodynia (the perception of pain from a normally innocuousstimulus), hyperalgesia (an exaggerated response to any given painstimulus) and an expansion of the receptive field (i.e. the area that is“painful” when a stimulus is applied), phantom pain or inflammatorypain. Acute pain types comprise, but are not limited to, pain associatedwith tissue damage, postoperative pain, pain after trauma, pain causedby burns, pain caused by local or systemic infection, visceral painassociated with diseases comprising: pancreatitis, intestinal cystitis,dysmenorrhea, Irritable bowel syndrome, Crohn's disease, ureteral colicand myocardial infarction. Furthermore, the term “pain” comprises painassociated with CNS disorders comprising: multiple sclerosis, spinalcord injury, traumatic brain injury, Parkinson's disease and stroke. Insome embodiments, “pain” relates to chronic pain types comprisingheadache (for example migraine disorders, episodic and chronictension-type headache, tension-type like headache, cluster headache, andchronic paroxysmal hemicrania), low back pain, cancer pain,osteoarthritis pain and neuropathic pain, but is not limited thereto.Inflammatory pain (pain in response to tissue injury and the resultinginflammatory process) as defined herein relates to inflammatory painassociated with diseases comprising connective tissue diseases,rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosisand arthritis, but is not limited thereto. Neuropathic pain (painresulting from damage to the peripheral nerves or to the central nervoussystem itself) includes conditions comprising, but not limited tometabolic neuropathies (e.g., diabetic neuropathy), post-herpeticneuralgia, trigeminal neuralgia, cranial neuralgia, post-strokeneuropathic pain, multiple sclerosis-associated neuropathic pain,HIV/AIDS-associated neuropathic pain, cancer-associated neuropathicpain, carpal tunnel-associated neuropathic pain, spinal cordinjury-associated neuropathic pain, complex regional pain syndrome,fibromyalgia-associated neuropathic pain, reflex sympathic dystrophy,phantom limb syndrome or peripheral nerve or spinal cord trauma, nervetransection including surgery, limb amputation and stump pain, paincaused by the side effects of anti-cancer and anti-AIDS therapies,post-surgical neuropathic pain, neuropathy-associated pain such as inidiopathic or post-traumatic neuropathy and mononeuritis, andneuropathic pain caused by connective tissue disease such as rheumatoidarthritis, Wallenberg's syndrome, systemic lupus erythematosus, multiplesclerosis, or polyarteritis nodosa. The neuropathy can be classified asradiculopathy, mononeuropathy, mononeuropathy multiplex, polyneuropathyor plexopathy.

In some embodiments, the application provides a use of a compound of theapplication for treatment of a musculoskeletal inflammatory disorder,including but not limited to low back pain, fibromyalgia, gout,osteoarthritis, rheumatoid arthritis, and tendinitis.

In some embodiments, the application provides a use of a compound of theapplication for treatment of a neuroinflammatory disorder, including butnot limited to Multiple Sclerosis (MS), which includes, but is notlimited to, for example, Relapse Remitting Multiple Sclerosis (RRMS),Secondary Progressive Multiple Sclerosis (SPMS), and Primary ProgressiveMultiple Sclerosis (PPMS); Parkinson's disease; Multiple System Atrophy(MSA); Corticobasal Degeneration; Progressive Supranuclear Paresis;Guillain-Barre Syndrome (GBS); and chronic inflammatory demyelinatingpolyneuropathy (CIDP).

In some embodiments, the application provides a use of a compound of theapplication for treatment of an airway inflammatory disorder, includingbut not limited to Kartagener syndrome, asthma (such as difficultasthma, or severe persistent asthma), vocal cord dysfunction (such asuncontrolled closing of the vocal cords while breathing), spasmodiccroup, reflexive vasomotor disease, and autonomic disorders.

In some embodiments, the application provides a use of a compound of theapplication for treatment of itch.

In some embodiments, the application provides a use of a compound of theapplication for treatment of dermatitis, including but not limited tocontact dermatitis, atopic dermatitis, seborrheic dermatitis, nummulardermatitis, exfoliative dermatitis, chronic dermatitis, stasisdermatitis, and perioral dermatitis.

In some embodiments, the application provides a use of a compound of theapplication for treatment of colitis, including but not limited toinflammatory bowel disease (IBD) colitis (Crohn's disease or ulcerativecolitis), microscopic colitis, chemical colitis, ischemic colitis,infectious colitis (food poisoning caused by infections, and infectionscaused by parasites or bacteria).

It is believed that antagonism of PAR2, in particular, is medicallyindicated for the treatment of the above-listed conditions. Byantagonism is meant blocking a receptor, in this case a PAR2 receptor,without causing it to transduce a signal. That is, antagonism results inblocking an endogenous or exogenous ligand from activating, or causingantagonism, of the receptor.

It is within ordinary skill to evaluate any compound disclosed andclaimed herein for effectiveness in modulation of PAR2 receptor and inthe various cellular assays using the procedures described above orfound in the scientific literature. Accordingly, the person of ordinaryskill can prepare and evaluate any of the claimed compounds withoutundue experimentation.

Any compound found to be an effective modulator, agonist or antagonist,can likewise be tested in animal models and in human clinical studiesusing the skill and experience of the investigator to guide theselection of dosages and treatment regimens.

In certain embodiments, the application comprises a method forconducting a pharmaceutical business, by determining an appropriateformulation and dosage of a compound of the application for treating orpreventing any of the diseases or conditions as described herein,conducting therapeutic profiling of identified formulations for efficacyand toxicity in animals, and providing a distribution network forselling an identified preparation as having an acceptable therapeuticprofile. In certain embodiments, the method further includes providing asales group for marketing the preparation to healthcare providers.

In certain embodiments, the application relates to a method forconducting a pharmaceutical business by determining an appropriateformulation and dosage of a compound of the application for treating orpreventing any of the disease or conditions as described herein, andlicensing, to a third party, the rights for further development and saleof the formulation.

The term “healthcare providers” refers to individuals or organizationsthat provide healthcare services to a person, community, etc. Examplesof “healthcare providers” include doctors, hospitals, continuing careretirement communities, skilled nursing facilities, subacute carefacilities, clinics, multispecialty clinics, freestanding ambulatorycenters, home health agencies, and HMO's.

Drug Combinations

The compounds of the present application may be used in pharmaceuticalcompositions or methods in combination with one or more additionalactive ingredients in the treatment of the diseases and disordersdescribed herein. Further additional active ingredients include othertherapeutics or agents that mitigate adverse effects of therapies forthe intended disease targets. Such combinations may serve to increaseefficacy, ameliorate other disease symptoms, decrease one or more sideeffects, or decrease the required dose of an inventive compound. Incertain embodiments, such combination provides an additive effect,wherein an additive effect refers to the sum of each of the effects ofindividual administration of the compound of the application and one ormore additional therapeutic agent(s). In other embodiments, suchcombination provides a synergistic effect, in which the therapeuticeffect exceeds the sum of each of the effects of individualadministration of the compound of the application and one or moreadditional therapeutic agent(s).

The additional active ingredients may be administered in a separatepharmaceutical composition from a compound of the present application ormay be included with a compound of the present application in a singlepharmaceutical composition. The additional active ingredients may beadministered simultaneously with, prior to, or after administration of acompound of the present application. Actual dosage levels of the activeingredients in the pharmaceutical compositions may be varied so as toobtain an amount of the active ingredient that is effective to achievethe desired therapeutic response for a particular subject, such as apatient, composition, and mode of administration, without being toxic tothe subject.

Combination agents include additional active ingredients that are knownor discovered to be effective in treating the diseases and disordersdescribed herein, including those active against another targetassociated with the disease. E.g., compositions and formulations of theapplication, as well as methods of treatment, can further comprise otherdrugs or pharmaceuticals, e.g., other active agents useful for treatingor palliative for the target diseases or related symptoms or conditions.The pharmaceutical compositions of the any compound described herein mayadditionally comprise one or more of such active agents, and methods oftreatment may additionally comprise administering an effective amount ofone or more of such active agents.

EXAMPLES

The following examples are offered to illustrate but not to limit theapplication. One of skill in the art will recognize that the followingsynthetic reactions and schemes may be modified by choice of suitablestarting materials and reagents in order to access other compounds ofthe application, or a pharmaceutically acceptable salt thereof.

Synthetic Protocols

Exemplary chemical entities useful in methods of the application willnow be described by reference to illustrative synthetic schemes fortheir general preparation below and the specific examples that follow.Artisans will recognize that, to obtain the various compounds herein,starting materials may be suitably selected so that the ultimatelydesired substituents will be carried through the reaction scheme with orwithout protection as appropriate to yield the desired product.Alternatively, it may be necessary or desirable to employ, in the placeof the ultimately desired substituent, a suitable group that may becarried through the reaction scheme and replaced as appropriate with thedesired substituent. Furthermore, one of skill in the art will recognizethat the transformations shown in the schemes below may be performed inany order that is compatible with the functionality of the particularpendant groups. Each of the reactions depicted in the general schemes ispreferably run at a temperature from about 0° C. to the refluxtemperature of the organic solvent used. Unless otherwise specified, thevariables are as defined above in reference to Formula (I), (I-A), or(I-B). Isotopically labeled compounds as described herein are preparedaccording to the methods described below, using suitably labeledstarting materials. Such materials are generally available fromcommercial suppliers of radiolabeled chemical reagents.

Terms and Abbreviations

-   ACN acetonitrile;-   aq aqueous;-   Atm atmospheric pressure;-   Boc t-butoxycarbonyl;-   Borax di-sodium tetraborate or sodium borate or sodium tetraborate;-   Cbz benzyloxycarbonyl;-   CDI 1,1′-carbonyldiimidazole;-   dba dibenzylideneacetone;-   DCM dichloromethane;-   DEA diethylamine;-   DIBAL-H diisobutylaluminium hydride;-   DIPEA diisopropylethylamine;-   DME 1,2-dimethoxyethane;-   DMF N,N-dimethyl formamide;-   DMSO dimethyl sulfoxide;-   Et₂O diethyl ether;-   EtOAc ethyl acetate;-   EtOH ethanol;-   eq. or equiv. equivalent;-   h hour(s);-   HATU 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium    hexafluorophosphate;-   HBTU O-benzotriazole-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HPLC high performance liquid chromatography;-   LCMS liquid chromatography mass spectrometry;-   LDA lithium diisopropylamide;-   LiHMDS lithium bis(trimethylsilyl)amide;-   MeOH methanol;-   min minute(s);-   MS mass spectrometry;-   MW microwave(s);-   NH₄OAc ammonium acetate;-   NMR nuclear magnetic resonance;-   ox oxidation;-   Psi pounds per square inch;-   quant. quantitative;-   RCM ring closing metathesis;-   r.t. room temperature;-   sat. saturated;-   SFC supercritical fluid chromatography;-   T3P propylphosphonic anhydride;-   TFA trifluoroacetic acid;-   THF tetrahydrofuran;-   TLC thin layer chromatography;-   TMEDA tetramethylethylenediamine;-   UPLC ultra performance liquid chromatography.-   LC-MS Conditions:

Method A:

LC-MS carried out using a Shimadzu LCMS-2020. UV detection=190-400 nm,mass spec=ESI. The column used was Ascentis express C18, 2.1 mm×50 mm,2.7 μm at 40° C. Flow rate was 1 ml/min using a solvent gradient of 5 to100% B over 1.8 minutes, where A=water (0.05% TFA) and B=acetonitrile(0.05% TFA). Where indicated, with designation base or modified to basiceluents or conditions, the mobile phases were made basic and replacedwith A=water+6.5 mM NH₄HCO₃ to pH10 in A, and B=acetonitrile (noadditive).

Method B:

UPLC-MS was carried out using a Waters Acquity UPLC and Waters SQD massspectrometer. UV detection=210-400 nm, mass spec=ESI withpositive/negative switching and cone voltage=10 V. The column used wasWaters Acquity HSS T3, 1.8 μm, 2.1×30 mm, at temperature 30° C. Flowrate was 1 ml/min using a solvent gradient of 2 to 98% B over 1.5minutes (total runtime with equilibration back to starting conditions 2min), where A=0.1% formic acid in water and B=0.1% formic acid inacetonitrile.

Method C:

Analytical HPLC chromatograms were performed using an Agilent 1100series instrument. The mass spectra were recorded with a WatersMicromass ZQ detector at 100° C. The mass spectrometer was equipped withan electrospray ion source (ESI) operated in a positive ion mode and wasset to scan between m/z 150-750 with a scan time of 0.3 s. Products andintermediates were analyzed by HPLC/MS on a Gemini (5.0 mM, 2.10×30 mm)using a high pH buffer gradient of 5% to 100% of ACN in H₂O (0.03%(NH₄)₂CO₃/0.375% NH₄OH) over 3.0 min at 1.8 mL/min for a 3.5 min run andon a Kinetex EVO (5.0 mM, 2.10×50 mm) using a low pH buffer gradient of5% to 100% of ACN in H₂O (0.05% HCOOH) over 2.8 min at 2.2 mL/min for a3.5 min run.

Method D:

Instruments: Waters Acquity H Class, Photo Diode Array, SQ Detector;Column: BEH C18, 1.7 micron, 2.1×50 mm; Gradient [time (min)/solvent Bin A (%)]: 0.00/5, 0.40/5, 0.8/35, 1.20/55, 2.50/100, 3.30/100 4.00/5;Solvents: solvent A=5 mM mmmonium acetate and 0.1% formic acid in H₂O;solvent B=0.1% formic acid in MeCN; Injection volume 2 μL; UV detection200 to 400 nM; Mass detection 100 to 1200 AMU (+ve electrospray); columnat ambient temperature; Flow rate 0.5 mL/min.

¹H NMR Spectroscopy:

The chemical shifts are reported in part-per-million from atetramethylsilane standard.

General Synthetic Scheme

Compounds of formula (I), (I-A) or (I-B) of the application can beprepared following the general synthetic scheme below:

General Procedure 1:

General Suzuki-Type Coupling (a to b, where Y=B(OH)2 or B(OR)2:

2-Bromo-4-fluorobenzaldehyde (5 g, 24.63 mmol) is added to propylboronicacid (3.25 g, 36.94 mmol), PdCl₂(dppf) (1.802 g, 2.46 mmol) and CS₂CO₃(16.05 g, 49.26 mmol) in dioxane (40 mL) and water (10 mL), then warmedto 80° C. under nitrogen. The resulting suspension is stirred at 80° C.for 12 hours. The reaction mixture is diluted with EtOAc (50 mL), andwashed sequentially with saturated brine (20 mL×3). The organic layer isdried over Na₂SO₄, filtered and evaporated to afford crude product. Thecrude product is purified by flash silica chromatography, elutiongradient 0 to 5% EtOAc in petroleum ether.

General Buchwald-Type Coupling (a to b, where Y=NH):

PdOAc₂ (553 mg, 2.46 mmol) is added to pyrrolidine (2.59 g, 36.9 mmol),BINAP (4.6 g, 7.4 mmol), CS₂CO₃ (16.05 g, 4.93 mmol) and2-bromo-4-fluorobenzaldehyde (5 g, 24.63 mmol) in toluene (50 mL) undernitrogen. The resulting solution is stirred at 120° C. for 1 hour. Thereaction mixture is filtered through celite. The solvent is removedunder reduced pressure. The crude product is purified by flash silicachromatography, elution gradient 0 to 1% EtOAc in petroleum ether.

General Stille-Type Coupling (a to b, where Y=SnBu3:

4-(Tributylstannyl)thiazole (1198 mg, 3.20 mmol) is added to a stirredsolution of 2-bromo-4-fluorobenzaldehyde (500 mg, 2.46 mmol) andbis(triphenylphosphine)palladium(II) chloride (104 mg, 0.15 mmol) in DMF(10 mL) under nitrogen. The resulting solution is stirred at 100° C. for16 hours. The solution is washed with brine and KF. The aqueous layer isextracted with EtOAc (2×20 mL). The solvent is removed under reducedpressure to afford crude product. The crude product is purified by flashsilica chromatography with EtOAc/petroleum ether (1:30).

General Alkylation of Aldehyde (b to c):

To the solution of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole(1.355 g, 6.83 mmol) in THF (30 mL) at −78° C. is added n-butyllithium(5.05 mL, 8.07 mmol) dropwise. The reaction mixture is stirred at −78°C. for 30 mins, then 4-fluoro-2-(pyrrolidin-1-yl)benzaldehyde (1.2 g,6.21 mmol) is added. The reaction is warmed up to RT and stirred at RTfor 1 hr. The reaction is then quenched with sat. NH₄Cl solution andextracted with EtOAc (3×60 mL). The organic layer is combined, washedwith water (60 mL), brine (60 mL), dried over MgSO4, filtered andconcentrated to give off-white solid.

General Deprotection Strategies:

Method 1:

To a solution of(4-fluoro-2-propylphenyl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol(11.6 g, 31.82 mmol) in DCM (50 mL) is added TFA (24.52 mL, 318.22mmol). The resulting solution is refluxed for 3 hrs and evaporated. Theresidue is redissolved in DCM (50 ml) and the solution is treated withsaturated NaHCO₃.

Method 2:

In a 125 mL pea-shaped flask is added(2-(2,5-dihydro-1H-pyrrol-1-yl)-4-fluorophenyl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol(3 g, 7.70 mmol) and HCl in dioxane (50 mL, 200 mmol) to give acolorless solution. The resulting mixture is stirred at rt for 30 hours.The solvent is removed under reduced pressure. The reaction mixture isquenched with saturated NaHCO₃ (150 mL), extracted with EtOAc (3×125mL), the organic layer is dried over Na₂SO₄, filtered and evaporated toafford yellow solid. The precipitate is washed with EtOAc (20 mL) anddried under vacuum

Method 3:

Hydrogen chloride/EtOAc (10 mL) is added to(4-fluoro-2-(oxazol-4-yl)phenyl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol(200 mg, 0.51 mmol) under nitrogen. The resulting mixture is stirred atrt for 36 hours. The solvent is removed under reduced pressure. Thecrude product is purified by preparative HPLC (Xselect CSH Fluoro phenylOBD column, 5 μm silica, 19 mm diameter, 100 mm length), usingdecreasingly polar mixtures of water (containing 0.05% Formic acid) andMeCN as eluents.

Method 4:

Combined alkylation/deprotection one-pot method: 2.50 M n-BuLi in THF(11.8 mL, 29.5 mmol) is added to a cooled solution of1-(diethoxymethyl)imidazole (5.02 g, 29.5 mmol) in THF (75 mL) at −45°C., and the mixture is stirred for 15 m. The mixture is cooled to −78°C., and a solution of 3-ethyl-8-fluoro-indolizine-5-carbaldehyde (2.82g, 14.8 mmol) in THF (25 mL) is added drop-wise. The mixture is stirredfor 30 m at −78° C. and then warmed to 0° C. for 1 h. The mixture isdiluted with 0.1M HCl (50.0 mL) and EtOAc (50.0 mL) at 0° C. The mixtureis stirred at 23° C. for 15 m. More EtOAc (50.0 mL) is added, and thephases were separated. The organic phase is extracted with 0.1M HCl(3×50.0 mL), and the combined aqueous phases are cautiously diluted withsat. NaHCO₃ (50.0 mL). The aqueous phase w is as extracted with EtOAc(3×200 mL), and the combined organic phases are washed with brine (200mL), dried over MgSO₄, filtered and concentrated under reduced pressure.

Method 5:

Perchlorostannane (130 mg, 0.50 mmol) is added to(3-cyclopropyl-8-fluoroindolizin-5-yl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol(200 mg, 0.50 mmol) in DCM (4 mL) under nitrogen. The resulting solutionis stirred at rt for 30 hours. The solvent is removed under reducedpressure and redissolved in MeOH (2 ml). The reaction mixture isneutralized with NH₃.H₂O to pH=7-8. The crude product is purified bypreparative HPLC (XSelect CSH Prep C18 OBD column, 5μ silica, 19 mmdiameter, 100 mm length), using decreasingly polar mixtures of water(containing 0.05% NH4HCO3) and MeCN as eluents.

Method 6:

Hydrogen chloride in dioxane (73.0 mL, 291.91 mmol) is added dropwise to(3-ethyl-7-fluorobenzofuran-4-yl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol(5.7 g, 14.60 mmol) in 1,4-dioxane (20 mL) in ice bath under nitrogen.The temperature is increased to room temperature naturally. Theresulting solution is stirred at 40° C. overnight. The solvent isremoved under reduced pressure to give a crude product. The crudeproduct is basified with 7M NH₃ in MeOH, and purified by flash C18-flashchromatography, elution gradient 0 to 30% MeCN in water.

General Procedure 2:

Heterocyclic aldehydes are synthesized and reacted in analagous fashionto General procedure 1 using similar protecting group and deprotectionprocedures.

Example 1. (4-Fluoro-2-propylphenyl)(1H-imidazol-2-yl)methanol

To a solution of(4-fluoro-2-propylphenyl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol(11.6 g, 31.82 mmol) in DCM (50 mL) was added TFA (24.52 mL, 318.22mmol). The resulting solution was refluxed for 3 hrs and evaporated. Theresidue was redissolved in DCM (50 ml) and the solution was treated withsaturated NaHCO₃. The precipitate was filtered and dried under vacuum togive (4-fluoro-2-propylphenyl)(1H-imidazol-2-yl)methanol (5.88 g, 79%)as an off-white solid. ¹H NMR (300 MHz, DMSO-d6) δ ppm 11.82 (br. s.,1H) 7.51 (dd, J=8.57, 6.31 Hz, 1H) 6.59-7.09 (m, 4H) 6.00 (d, J=4.33 Hz,1H) 5.90 (d, J=4.33 Hz, 1H) 2.63-2.84 (m, 1H) 2.52-2.62 (m, 1H)1.31-1.63 (m, 2H) 0.90 (t, J=7.25 Hz, 3H). LC-MS (Method B): m/z (ES+),[M+H]+=235; TFA, HPLC t_(R)=0.57 min.

Intermediate C:(4-Fluoro-2-propylphenyl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol

To a stirred solution of 4-fluoro-2-propylbenzaldehyde (302 mg, 1.82mmol) in THF (5 mL) at −78° C., was added a mixture of1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (400 mg, 2.02 mmol),n-BuLi (258 mg, 4.03 mmol) in THF (5 mL) over a period of 1 minute undernitrogen. The resulting solution was stirred at −78° C. for 1 hour. Thetemperature was increased to room temperature over a period of severalhours. The reaction mixture was quenched with saturated NH₄Cl (5 mL),extracted with DCM (3×10 mL). The organic layer was dried over Na₂SO₄,filtered and evaporated to afford a yellow oil. The residue was purifiedby preparative TLC (EtOAc:petroleum ether=1:2), to afford(4-fluoro-2-propylphenyl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol(C, 400 mg, 54.4%) as an orange oil. ¹H NMR (300 MHz, CDCl₃-d) δ ppm7.21 (dd, J=8.57, 5.93 Hz, 1H) 7.05 (dd, J=16.48, 1.41 Hz, 2H) 6.79-6.98(m, 2H) 6.16 (s, 1H) 4.90-5.15 (m, 2H) 3.20-3.45 (m, 2H) 2.60-2.87 (m,2H) 1.46-1.75 (m, 2H) 1.00 (t, J=7.25 Hz, 3H) 0.72-0.89 (m, 2H)−0.09-0.03 (m, 9H). LC-MS (Method A): m/z (ES+), [M+H]+=365; acid, HPLCt_(R)=1.062 min.

Intermediate B: 1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-imidazole

Sodium hydride (0.529 g, 22.03 mmol) in THF (50 mL) was cooled to 0° C.over a period of 10 minutes under nitrogen. To this was slowly addedimidazole (1 g, 14.69 mmol) in THF (30 mL) were under nitrogen. Thetemperature was increased to room temperature gradually. The resultingmixture was stirred at 25° C. for 30 minutes, and then(2-(chloromethoxy)ethyl)trimethylsilane (3.67 g, 22.03 mmol) was addedslowly to the mixture at 0° C. over a period of 1 minute under nitrogen.The temperature was increased to room temperature gradually. Theresulting mixture was stirred at 25° C. for 14 hours. The mixture wasconcentrated and diluted with EtOAc (200 mL), and washed sequentiallywith water (150 mL). The organic layer was dried over Na₂SO₄, filteredand evaporated to afford crude product. The crude product was purifiedby flash C18-flash chromatography with an elution gradient 0 to 50% MeCNin water. Pure fractions were evaporated to dryness to afford1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (B, 2.91 g, 100%) as awhite oil which solidified on standing. 1H δ NMR (DMSO-d6, 300 MHz,) δ−0.05-0.05 (9H, d, J=6.9 Hz), 0.83-0.97 (2H, m), 3.52-3.64 (2H, m),5.54-5.61 (2H, s), 7.70-7.78 (1H, s), 7.84-7.91 (1H, s), 9.25-9.31 (1H,s). LC-MS (Method A): m/z (ES+), [M+H]+=199; HPLC t_(R)=1.177 min.

Intermediate A: 4-Fluoro-2-propylbenzaldehyde

2-Bromo-4-fluorobenzaldehyde (5 g, 24.63 mmol) was added topropylboronic acid (3.25 g, 36.94 mmol), PdCl₂(dppf) (1.802 g, 2.46mmol) and CS₂CO₃ (16.05 g, 49.26 mmol) in dioxane (40 mL) and water (10mL), then warmed to 80° C. under nitrogen. The resulting suspension wasstirred at 80° C. for 12 hours. The reaction mixture was diluted withEtOAc (50 mL), and washed sequentially with saturated brine (20 mL×3).The organic layer was dried over Na₂SO₄, filtered and evaporated toafford crude product. The crude product was purified by flash silicachromatography, elution gradient 0 to 5% EtOAc in petroleum ether. Purefractions were evaporated to dryness to afford4-fluoro-2-propylbenzaldehyde (A, 3.10 g, 76%) as a pale yellow liquid.¹H NMR (400 MHz, DMSO-d6) δ ppm 0.93 (3H, t, J=7.3), 1.58 (2H, m),2.96-3.05 (2H, m), 7.21-7.32 (2H, m), 7.93 (1H, dd, J=8.2, 6.3), 10.20(1H, s).

Example 2 and 3. (R)-(4-fluoro-2-propylphenyl)(1H-imidazol-2-yl)methanol(2) and (S)-(4-Fluoro-2-propylphenyl)(1H-imidazol-2-yl)methanol (3)

The racemic mixture of Example 1 was separated by chiral SFC using achiralpak AD-H column (30×250 mm, 5 μm). The mobile phase A wassupercritical CO₂, and Mobile phase B was isopropanol containing 0.1%dimethylamine. A gradient of up to 15% B was run at 2.8 mL/min and twopeaks were isolated to give(R)-(4-fluoro-2-propylphenyl)(1H-imidazol-2-yl)methanol (Peak 1 at 3.25min, 2.490 g, 33.4% and >99% ee, Example 2) and(S)-(4-fluoro-2-propylphenyl)(1H-imidazol-2-yl)methanol (Peak 2 at 4.54min, 2.480 g, 33.3% and >99% ee, Example 3) as white solids. Absolutestereochemistry was assigned based on a crystal structure of thecompound with PAR2 receptor.

Example 2 Analytical data: ¹H NMR (300 MHz, DMSO-d6) δ ppm 11.83 (br.s., 1H) 7.51 (dd, J=8.48, 6.22 Hz, 1H) 6.61-7.06 (m, 4H) 6.00 (br. s.,1H) 5.90 (s, 1H) 2.64-2.78 (m, 1H) 2.52-2.62 (m, 1H) 1.35-1.63 (m, 2H)0.90 (t, J=7.35 Hz, 3H). LC-MS (Method A): [M+H]+=235; HPLC t_(R)=0.57min. Chiral SFC t_(R)=3.25 min.

Example 3 Analytical data: ¹H NMR (300 MHz, DMSO-d6) δ ppm 11.83 (br.s., 1H) 7.51 (dd, J=8.57, 6.31 Hz, 1H) 6.65-7.05 (m, 4H) 5.81-6.22 (m,2H) 2.64-2.78 (m, 1H) 2.53-2.62 (m, 1H) 1.35-1.62 (m, 2H) 0.90 (t,J=7.35 Hz, 3H). LC-MS (Method A): [M+H]+=235; HPLC t_(R)=0.57 min.Chiral SFC t_(R)=4.54 min

Example 4. (2-Cyclopentenylphenyl)(1H-imidazol-2-yl)methanol

(2-Cyclopentenylphenyl)(1H-imidazol-2-yl)methanol was made in analogousfashion to Example 1, using2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and2-bromo-benzaldehyde. ¹H NMR (400 MHz, DMSO): δ ppm 1.89-1.97 (m, 2H),2.50-2.56 (m, 2H), 2.67-3.32 (m, 2H), 5.94-6.03 (m, 3H), 6.74-6.76 (d,1H), 6.97 (s, 1H), 7.15-7.24 (m, 3H), 7.53-7.55 (m, 1H). LC-MS (MethodA): m/z (ES+), [M+H]+=241; base, HPLC t_(R)=1.420 min.

Example 5. (2-Cyclopentenyl-4-fluorophenyl)(1H-imidazol-2-yl)methanol

(2-Cyclopentenyl-4-fluorophenyl)(1H-imidazol-2-yl)methanol was preparedin analogous fashion using and to Example 1 using2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane toprovide a white solid (68 mg, 68%). ¹H NMR (400 MHz, DMSO): δ ppm1.87-1.96 (m, 2H), 2.32-2.49 (m, 2H), 2.66-2.71 (m, 2H), 5.75 (s, 1H),5.90-5.91 (d, 1H), 5.99-6.06 (m, 1H), 6.75 (s, 1H), 6.97-6.99 (m, 2H),7.00-7.09 (m, 1H), 7.54-7.58 (m, 1H). LC-MS (Method A): m/z (ES+),[M+H]+=259; base, HPLC t_(R)=2.185 min.

Example 6. (2-Cyclopentyl-4-fluorophenyl)(1H-imidazol-2-yl)methanol

To a stirred solution of(2-(cyclopent-1-en-1-yl)-4-fluorophenyl)(1H-imidazol-2-yl)methanol (254mg, 0.98 mmol) in MeOH (10 mL) was stirred under an atmosphere ofhydrogen (5 atm) and 70° C. for 12 hours. The reaction mixture wasfiltered through celite. The solvent was removed under reduced pressure.The residue was purified by preparative TLC (DCM:MeOH=10:1), to afford(2-cyclopentyl-4-fluorophenyl)(1H-imidazol-2-yl)methanol (48.6 mg,18.99%) as a white solid. ¹H NMR (400 MHz, DMSO): δ ppm 1.40-1.61 (m,4H), 1.65-1.75 (m, 3H), 1.88-1.91 (m, 1H), 3.32-3.40 (m, 1H), 5.97 (s,1H), 6.05 (s, 1H), 6.75 (s, 1H), 6.94-7.03 (m, 3H), 7.46-7.48 (m, 1H).LC-MS (Method A): m/z (ES+), [M+H]+=261; base, HPLC t_(R)=2.286 min.

Example 7. (2-Cyclobutyl-4-fluorophenyl)(1H-imidazol-2-yl)methanol

(2-Cyclobutyl-4-fluorophenyl)(1H-imidazol-2-yl)methanol was prepared inanalogous fashion using and to Example 1 using cyclobutylzinc(II)bromide to provide a white solid (55 mg, 61%). ¹H (300 MHz, DMSO-d6) δppm 1.76 (1H, d, J=9.2 Hz), 1.81-1.96 (1H, m), 1.93-2.12 (3H, m), 2.30(1H, d, J=10.7 Hz), 3.79 (1H, q, J=8.9 Hz), 5.84 (1H, d, =J 4.3 Hz),6.00 (1H, d, J=4.4 Hz), 6.74 (1H, s), 6.94-7.03 (2H, m), 7.07 (1H, dd,J=10.9, 2.7 Hz), 7.48 (1H, dd, J=8.6, 6.3 Hz), 11.80 (1H, s). LC-MS(Method A): m/z (ES+), [M+H]+=247; t_(R)=0.79 min.

Example 8.(E)-(4-Fluoro-2-(prop-1-enyl)phenyl)(1H-imidazol-2-yl)methanol

(E)-(4-Fluoro-2-(prop-1-enyl)phenyl)(1H-imidazol-2-yl)methanol wasprepared in analogous fashion using (E)-prop-1-enylboronic acid. ¹H NMR(400 MHz, DMSO-d₆) δ: 1.84 (dd, J=1.5, 6.5 Hz, 3H), 5.93 (d, J=4.0 Hz,1H), 6.11 (d, J=4.0 Hz, 1H), 6.17-6.26 (m, 1H), 6.80-6.84 (m, 2H), 6.97(br. s, 1H), 7.03 (td, J=3.0, 8.5 Hz, 1H), 7.22 (dd, J=2.5, 11.0 Hz,1H), 7.46 (dd, J=6.5, 8.5 Hz, 1H), 11.91 (br. s, 1H). LCMS (Method D):m/z 233 (M+H)⁺ (ES⁺), t_(R)=1.53 min.

Example 9.(Z)-(4-Fluoro-2-(prop-1-enyl)phenyl)(1H-imidazol-2-yl)methanol

(Z)-(4-Fluoro-2-(prop-1-enyl)phenyl)(1H-imidazol-2-yl)methanol wasprepared in analogous fashion using (Z)-prop-1-enylboronic acid. ¹H NMR(500 MHz, MeOD) δ 7.53 (dd, J=8.6, 5.9 Hz, 1H), 7.01 (td, J=8.6, 2.7 Hz,1H), 6.95 (s, 2H), 6.89 (dd, J=9.7, 2.7 Hz, 1H), 6.47 (d, J=11.1 Hz,1H), 5.95 (s, 1H), 5.83 (dq, J=11.5, 7.0 Hz, 1H), 1.62 (dd, J=7.0, 1.6Hz, 3H). LC-MS (Method C): m/z (ES+), [M−H₂O+H]⁺=215.3.

Example 10. (3,4-Difluoro-2-propylphenyl)(1H-imidazol-2-yl)methanol

(3,4-Difluoro-2-propylphenyl)(1H-imidazol-2-yl)methanol was prepared inanalogous fashion to Example 1 using 2-bromo-3,4-difluorobenzaldehydeand propylboronic acid (750 mg, 60%). LC-MS (Method A): m/z (ES+),[M+H]+=253; HPLC t_(R)=1.416 min.

Example 11. Peak 1, Pure enantiomer of(3,4-Difluoro-2-propylphenyl)(1H-imidazol-2-yl)methanol

Racemic material from Example 10 was subjected to chiral SFC usingEnantioCel-C1, (21.2×250 mm) with a mobile Phase A:CO₂, Mobile Phase B:EtOH (0.1% IPA) at an 80:20 ratio. Flow rate: 40 mL/min. ¹HNMR (400 MHz,Methanol-d4) δ −0.15-0.20 (3H, s), 0.93-0.98 (2H, t, J=7.3), 1.30-1.51(2H, dtd, J=30.2, 16.4, 15.1, 6.7), 2.65-2.76 (2H, m), 5.99-6.04 (1H,s), 6.94-7.17 (3H, m), 7.26-7.34 (1H, m). Chiral SFC t_(R)=4.1 min.

Example 12. Peak 2, pure enantiomer(3,4-Difluoro-2-propylphenyl)(1H-imidazol-2-yl)methanol

Racemic material from Example 10 was subjected to chiral SFC usingEnantioCel-C1, (21.2×250 mm) with a mobile Phase A:CO₂, Mobile Phase B:EtOH (0.1% IPA) at an 80:20 ratio. Flow rate: 40 mL/min. ¹HNMR (400 MHz,Methanol-d4) δ 0.91-1.00 (3H, t, J=7.3), 1.29-1.52 (2H, m), 2.65-2.76(2H, m), 5.99-6.04 (1H, s), 6.97-7.02 (2H, s), 7.05-7.17 (1H, m),7.26-7.34 (1H, m). Chiral SFC t_(R)=5.5 min.

Example 13. (3-Chloro-2-propylphenyl)(1H-imidazol-2-yl)methanol

(3-Chloro-2-propylphenyl)(1H-imidazol-2-yl)methanol was prepared inanalogous fashion to Example 1 using 2-bromo-3-chlorobenzaldehyde andpropylboronic acid. ¹HNMR (300 MHz, DMSO-d6) δ 0.93 (3H, t, J=7.3), 1.35(2H, m), 2.68 (1H, dt, J=13.1, 6.5), 2.76-2.93 (1H, m), 5.93 (1H, d,J=4.4), 6.16 (1H, d, J=4.3), 6.75 (1H, s), 6.98 (1H, s), 7.22 (1H, d,J=7.8), 7.29-7.34 (1H, m), 7.50 (1H, dd, J=7.7, 1.3), 11.90 (1H, s).LC-MS (Method A): m/z (ES+), base [M+H]+=251; HPLC t_(R)=1.53 min.

Example 14.(4-Fluoro-2-(pyrrolidin-1-yl)phenyl)(1H-imidazol-2-yl)methanol

To the solution of(4-fluoro-2-(pyrrolidin-1-yl)phenyl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol(2.2 g, 5.62 mmol) in DCM (30 mL) was added TFA (43.3 mL, 561.86 mmol).The reaction was stirred at RT for 6 hr. TFA was removed. The residuewas partitioned between EtOAc (30 mL) and sat. NaHCO3 (30 mL). Theorganic layer was collected, washed with water (30 mL), brine (30 mL),dried over MgSO4, filtered and concentrated. The residue was purifiedvia combiflash (10:1 DCM/MeOH, 80 g column) to give off-white solid. ¹HNMR (300 MHz, DMSO-d6) δ ppm 1.75-1.96 (m, 4H) 3.04-3.29 (m, 4H)5.79-5.95 (m, 1H) 6.00-6.12 (m, 1H) 6.53-7.14 (m, 4H) 7.18-7.47 (m, 1H)11.67-11.96 (m, 1H). LC-MS (Method B): m/z (ES+), [M+H]+=262; TFA, HPLCt_(R)=0.54 min

Intermediate C:(4-Fluoro-2-(pyrrolidin-1-yl)phenyl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol

To the solution of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole(1.355 g, 6.83 mmol) in THF (30 mL) at −78° C. was added n-butyllithium(5.05 mL, 8.07 mmol) dropwise. The reaction mixture was stirred at −78°C. for 30 mins, then 4-fluoro-2-(pyrrolidin-1-yl)benzaldehyde (1.2 g,6.21 mmol) was added. The reaction was warmed up to RT and stirred at RTfor 1 hr. The reaction was then quenched with sat. NH₄Cl solution andextracted with EtOAc (3×60 mL). The organic layer was combined, washedwith water (60 mL), brine (60 mL), dried over MgSO4, filtered andconcentrated to give off-white solid. ¹H NMR (300 MHz, DMSO-d6) δ 0.00(s, 10H) 0.72-1.02 (m, 2H) 1.71-1.94 (m, 4H) 2.80-3.14 (m, 4H) 3.44-3.59(m, 2H) 5.10-5.27 (m, 1H) 5.34-5.38 (m, 1H) 5.46-5.61 (m, 1H) 5.74-5.91(m, 1H) 6.04-6.24 (m, 1H) 6.60-6.84 (m, 3H) 7.16-7.31 (m, 1H) 7.42-7.61(m, 1H). LC-MS (Method B): m/z (ES+), [M+H]+=392; TFA, HPLC t_(R)=0.98min.

Intermediate B: See Example 1 Intermediate C:4-Fluoro-2-(pyrrolidin-1-yl)benzaldehyde

PdOAc₂ (553 mg, 2.46 mmol) was added to pyrrolidine (2.59 g, 36.9 mmol),BINAP (4.6 g, 7.4 mmol), CS₂CO₃ (16.05 g, 4.93 mmol) and2-bromo-4-fluorobenzaldehyde (5 g, 24.63 mmol) in toluene (50 mL) undernitrogen. The resulting solution was stirred at 120° C. for 1 hour. Thereaction mixture was filtered through celite. The solvent was removedunder reduced pressure. The crude product was purified by flash silicachromatography, elution gradient 0 to 1% EtOAc in petroleum ether. Purefractions were evaporated to dryness to afford4-fluoro-2-(pyrrolidin-1-yl)benzaldehyde (3.6 g, 76%) as a white solid.¹H NMR (CDCl₃, 400 MHz) δ 10.03 (s, 1H), 7.76-7.72 (m, 1H), 6.57-6.53(m, 2H), 3.41-3.36 (t, 4H), 2.07-2.00 (t, 4H). m/z (ES+), [M+H]+=194.0;acid, HPLC t_(R)=0.925 min.

Example 15. Isomer 1, pure enantiomer(4-Fluoro-2-(pyrrolidin-1-yl)phenyl)(1H-imidazol-2-yl)methanol

The racemic mixture of Example 14 was separated by chiral HPLC to givePeak 1 and Peak 2 as white solids. ¹H NMR (300 MHz, DMSO-d6) δ ppm1.75-2.01 (m, 4H) 2.97-3.33 (m, 9H) 5.69-5.95 (m, 1H) 5.99-6.09 (m, 1H)6.48-6.80 (m, 2H) 6.78-7.00 (m, 2H) 7.17-7.47 (m, 1H) 11.65-12.13 (m,1H). LC-MS (Method B): [M+H]+=262; TFA, HPLC t_(R)=0.55 min. Chiralpurity was determined using a Lux Amylose-2 column (4.6×250 mm, 5 μm).Mobile phase A was hexane and Mobile Phase B was a 1:1methanol:isopropanol mixture. To this was added a 0.1% diethylamineadditive. The column was run at 1 ml/min with detection at 220 nM. Peak1 eluted at 6.12 min>98% ee.

Example 16. Isomer 2, pure enantiomer(4-Fluoro-2-(pyrrolidin-1-yl)phenyl)(1H-imidazol-2-yl)methanol

The racemic mixture of Example 14 was separated by chiral HPLC to givePeak 1 and Peak 2 as white solids. ¹H NMR (300 MHz, DMSO-d6) δ ppm1.72-2.05 (m, 5H) 2.98-3.32 (m, 7H) 5.67-5.96 (m, 1H) 5.98-6.16 (m, 1H)6.52-6.79 (m, 3H) 6.73-7.03 (m, 2H) 7.17-7.38 (m, 1H) 11.67-12.12 (m,1H). LC-MS (Method B): [M+H]+=262; TFA, HPLC t_(R)=0.55 min Chiralpurity was determined using a Lux Amylose-2 column (4.6×250 mm, 5 u).Mobile phase A was hexane and Mobile Phase B was a 1:1methanol:isopropanol mixture. To this was added a 0.1% diethylamineadditive. The column was run at 1 mL/min with detection at 220 nm. Peak2 eluted at 7.29 min with >98% ee.

Example 17.(2-(2,5-dihydro-1H-pyrrol-1-yl)-4-fluorophenyl)(1H-imidazol-2-yl)methanol

In a 125 mL pea-shaped flask was added(2-(2,5-dihydro-1H-pyrrol-1-yl)-4-fluorophenyl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol(3 g, 7.70 mmol) and HCl in dioxane (50 mL, 200 mmol) to give acolorless solution. The resulting mixture was stirred at rt for 30hours. The solvent was removed under reduced pressure. The reactionmixture was quenched with saturated NaHCO₃ (150 mL), extracted withEtOAc (3×125 mL), the organic layer was dried over Na₂SO₄, filtered andevaporated to afford yellow solid. The precipitate was washed with EtOAc(20 mL) and dried under vacuum to afford(2-(2,5-dihydro-1H-pyrrol-1-yl)-4-fluorophenyl)(1H-imidazol-2-yl)methanol(1.00 g, 50.1%) as a white solid, which was used without furtherpurification. ¹H NMR (300 MHz, MeOD) δ ppm 4.06 (4H, s), 5.86 (2H, s),6.25 (1H, s), 6.60 (1H, td), 6.74 (1H, dd), 6.94 (2H, s), 7.20 (1H, dd).LC-MS (Method A): m/z (ES+), [M+H]+=260; acid, HPLC t_(R)=0.592 min.

(2-(2,5-Dihydro-1H-pyrrol-1-yl)-4-fluorophenyl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanolwas prepared in analogous fashion to Example 14, using2,5-dihydro-1H-pyrrole.

Example 18. Isomer 1, Pure Enantiomer(2-(2,5-dihydro-1H-pyrrol-1-yl)-4-fluorophenyl)(1H-imidazol-2-yl)methanol

Example 17 was purified by preparative chiral-HPLC (Column: CHIRALPAKAD-H SFC, 5×25 cm, 5 μm; Mobile Phase A:CO₂:6% 0, Mobile Phase B: EtOH(0.1% IPA)—40%; Flow rate: 160 mL/min; 215 nm detection. ¹H NMR (300MHz, MeOD) δ ppm 4.12 (4H, s), 5.92 (2H, s), 6.31 (1H, s), 6.66 (1H,td), 6.80 (1H, dd), 7.00 (2H, s), 7.26 (1H, dd). LC-MS (Method A): m/z(ES+), [M+H]+=260; acid, HPLC t_(R)=1.306 min. Chiral SFC t_(R)=5.45 min(peak 1). >98% ee

Example 19. Isomer 2, Pure Enantiomer(2-(2,5-dihydro-1H-pyrrol-1-yl)-4-fluorophenyl)(1H-imidazol-2-yl)methanol

Example 17 was purified by preparative chiral-HPLC (Column: CHIRALPAKAD-H SFC, 5×25 cm, 5 μm; Mobile Phase A:CO₂:6%0, Mobile Phase B: EtOH(0.1% IPA)—40%; Flow rate: 160 mL/min; 215 nm detection. ¹H NMR (300MHz, MeOD) δ ppm 4.12 (3H, s), 5.92 (2H, s), 6.31 (1H, s), 6.66 (1H,td), 6.80 (1H, dd), 7.01 (2H, s), 7.26 (1H, dd). LC-MS (Method A): m/z(ES+), [M+H]+=260; acid, HPLC t_(R)=1.30 min Chiral SFC t_(R)=7.60 min(peak 2). >98% ee.

Example 20. (2-(Azetidin-1-yl)-4-fluorophenyl)(1H-imidazol-2-yl)methanol

An analogous procedure to Example 14 was employed using azetidine toprovide (2-(azetidin-1-yl)-4-fluorophenyl)(1H-imidazol-2-yl)methanol (17mg, 12%). ¹H NMR (300 MHz, CDCl₃) δ ppm 7.17 (dd, J=7.08, 8.59 Hz, 1H),6.91 (s, 2H), 6.47 (dt, J=2.55, 8.45 Hz, 1H), 6.18 (dd, J=2.64, 12.09Hz, 1H), 5.78-5.91 (m, 2H), 3.78-4.06 (m, 4H), 2.05-2.29 (m, 2H),2.05-2.29 (m, 2H), 2.20 (quin, J=7.27 Hz, 2H). LC-MS (Method B):[M+H]+=248; TFA, HPLC t_(R)=0.35 min.

Example 21.(3-Chloro-2-(1H-pyrazol-1-yl)phenyl)(1H-imidazol-2-yl)methanol

2,2,2-Trifluoroacetic acid (2.5 mL, 32.45 mmol) was added to(3-chloro-2-(1H-pyrazol-1-yl)phenyl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol(200 mg, 0.49 mmol) in DCM (5 mL). The resulting solution was stirred atrt. for 18 hours. The solvent was removed under reduced pressure. Thereaction mixture was neutralized with saturated NaHCO₃, extracted withEtOAc (3×5 mL), filtered and evaporated to afford white solid. The crudeproduct was purified by flash C18-flash chromatography, elution gradient5 to 70% MeCN in water. Pure fractions were evaporated to dryness toafford (3-chloro-2-(1H-pyrazol-1-yl)phenyl)(1H-imidazol-2-yl)methanol(45 mg, 33%) as a white solid. ¹H NMR (300 MHz, DMSO) δ ppm 5.24-5.26(m, 1H), 6.21-6.22 (m, 1H), 6.42-6.43 (m, 1H), 6.86 (s, 2H), 7.52-7.60(m, 2H), 7.65-7.68 (m, 2H), 7.73 (s, 1H), 11.86 (s, 1H). LC-MS (MethodA): m/z (ES+), [M+H]+=275.1; acid, HPLC t_(R)=0.477 min.

Intermediate D,(3-Chloro-2-(1H-pyrazol-1-yl)phenyl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol

n-Butyllithium (0.774 mL, 1.94 mmol) was added slowly to1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (384 mg, 1.94 mmol) inTHF (6 mL) at −78° C. under nitrogen. 0.5 hour later, was added3-chloro-2-(1H-pyrazol-1-yl)benzaldehyde (200 mg, 0.97 mmol). Theresulting solution was stirred at −78° C. for 1.5 hours. The reactionmixture was quenched with saturated NH₄Cl (5 mL), extracted with EtOAc(3×10 mL), the organic layer was dried over Na₂SO₄, filtered andevaporated to afford white liquid. The crude product was purified byflash C18-flash chromatography, elution gradient 5 to 70% MeCN in water.Pure fractions were evaporated to dryness to afford(3-chloro-2-(1H-pyrazol-1-yl)phenyl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol(380 mg, 97%) as a white liquid. ¹H NMR (400 MHz, DMSO) δ −0.05-0.02 (m,24H), 0.70-0.78 (m, 1H), 0.81-0.85 (m, 4H), 3.18-3.24 (m, 2H), 3.43-3.47(m, 3H), 5.01-5.03 (m, 1H), 5.27-5.29 (m, 1H), 5.32 (s, 3H), 5.52-5.54(m, 1H), 6.23-6.24 (m, 1H), 6.29 (s, 1H), 6.72 (s, 1H), 6.93 (s, 2H),7.14 (s, 1H), 7.26 (s, 2H), 7.59-7.60 (m, 2H), 7.67 (s, 1H), 7.77 (s,2H), 7.81-7.82 (m, 1H).

Intermediate C, 3-Chloro-2-(1H-pyrazol-1-yl)benzaldehyde

DIBAL-H (3.39 mL, 3.39 mmol) was added slowly to3-chloro-N-methoxy-N-methyl-2-(1H-pyrazol-1-yl)benzamide (600 mg, 2.26mmol) in THF (10 mL) at −78° C. under nitrogen. The resulting solutionwas stirred at −40° C. for 2 hours. The reaction mixture was poured intowater (10 mL), extracted with EtOAc (3×15 mL), the organic layer wasdried over Na₂SO₄, filtered and evaporated to afford white solid. Thecrude product was purified by flash silica chromatography, elutiongradient 0 to 10% EtOAc in petroleum ether. Pure fractions wereevaporated to dryness to afford 3-chloro-2-(1H-pyrazol-1-yl)benzaldehyde(345 mg, 73.9%) as a white solid. ¹H NMR (300 MHz, DMSO) δ 6.63-6.64 (m,1H), 7.66-7.75 (m, 1H), 7.84-7.91 (m, 2H), 8.01-8.04 (m, 1H), 8.24-8.25(m, 1H), 9.21 (s, 1H). LC-MS (Method A): m/z (ES+), [M+H]+=207; acid,HPLC t_(R)=0.788 min.

Intermediate B, 3-Chloro-N-methoxy-N-methyl-2-(1H-pyrazol-1-yl)benzamide

DIEA (0.941 mL, 5.39 mmol) was added slowly to3-chloro-2-(1H-pyrazol-1-yl)benzoic acid (200 mg, 0.90 mmol), HATU (512mg, 1.35 mmol) and N,O-dimethylhydroxylamine hydrochloride (219 mg, 2.25mmol) in DMF (5 mL) at 0° C. over a period of 6 minutes under nitrogen.The temperature was increased to room temperature naturally. Theresulting solution was stirred at rt. for 2 hours. The reaction mixturewas diluted with water, extracted with EtOAc (3×10 mL), washed withsaturated brine (15 mL), the organic layer was dried over Na₂SO₄,filtered and evaporated to afford white solid. The crude product waspurified by flash silica chromatography, elution gradient 0 to 50% EtOAcin petroleum ether. Pure fractions were evaporated to dryness to afford3-chloro-N-methoxy-N-methyl-2-(1H-pyrazol-1-yl)benzamide (210 mg, 88%)as a white solid. ¹H NMR (300 MHz, DMSO) δ 2.95-3.01 (m, 3H), 3.45 (m,3H), 6.46 (s, 1H), 7.51-7.60 (m, 2H), 7.68-7.77 (m, 2H), 7.91-7.95 (m,3H). LC-MS (Method A): m/z (ES+), [M+H]+=266; acid, HPLC t_(R)=0.717min.

Intermediate A, 3-Chloro-2-(1H-pyrazol-1-yl)benzoic acid

2-Bromo-3-chlorobenzoic acid (500 mg, 2.12 mmol), 1H-pyrazole (145 mg,2.12 mmol), N1,N2-dimethylcyclohexane-1,2-diamine (15.1 mg, 0.11 mmol),copper(I) iodide (60.7 mg, 0.32 mmol), K₂CO₃ (734 mg, 5.31 mmol) andL-proline (73.3 mg, 0.64 mmol) were added to DMSO (6 mL) at 25° C. undernitrogen. The resulting mixture was stirred at 100° C. for 1 hour. Thereaction mixture was diluted with water (10 mL), extracted with EtOAc(2×10 mL), the organic layer was dried over Na₂SO₄, filtered andevaporated to afford white liquid. The crude product was purified byflash silica chromatography, elution gradient 0 to 10% EtOAc inpetroleum ether. Pure fractions were evaporated to dryness to afford3-chloro-2-(1H-pyrazol-1-yl)benzoic acid (250 mg, 52.8%) as a white oil.¹H NMR (400 MHz, DMSO) δ ppm 6.46 (s, 1H), 7.41-7.50 (m, 1H), 7.58-7.62(m, 1H), 7.66-7.67 (m, 1H), 7.75-7.77 (m, 1H), 7.81-7.83 (m, 1H), 7.96(s, 1H). LC-MS (Method A): m/z (ES+), [M+H]+=222.9; acid, HPLCt_(R)=0.54 min.

Example 22.(3,4-Difluoro-2-(1H-pyrazol-1-yl)phenyl)(1H-imidazol-2-yl)methanol

Example 22 was prepared in an analogous fashion to Example 21, using2-bromo-3,4-difluorobenzoic acid and 1H-pyrazole. ¹H NMR (300 MHz,DMSO-d6) δ ppm 5.47-5.49 (m, 1H), 6.27-6.29 (m, 1H), 6.48-6.50 (m, 1H),6.73 (s, 1H), 6.96 (s, 1H), 7.49-7.54 (m, 1H), 7.60-7.68 (m, 1H),7.78-7.79 (m, 1H), 7.93-7.94 (m, 1H) 11.91 (s, 1H). LC-MS (Method A):m/z (ES+), [M+H]+=277; acid, HPLC t_(R)=0.656 min.

Example 23.(4-Fluoro-2-(1H-pyrazol-1-yl)phenyl)(1H-imidazol-2-yl)methanol

Example 23 was prepared in analogous fashion to Example 21, using2-bromo, 4-fluorbenzoic acid ester and 1H-pyrazole. (In this case,resultant DIBAL-H reduction on the ester led to the alcohol and not thealdehyde. An additional step was needed to oxidize the benzyl alcohol tothe aldehyde using 20 equivalents of MnO₂ in DCM.)¹H NMR (400 MHz,DMSO-d6) δ ppm 5.80 (1H, s), 6.53 (1H, t), 6.89 (2H, d), 7.25-7.35 (2H,m), 7.69 (1H, dd), 7.78 (1H, d), 8.41 (1H, d), 12.05 (1H, s). LC-MS(Method A): m/z (ES+), [M+H]+=259; HPLC t_(R)=0.609 min.

The following examples were made by analogous routes to Example 14,using chiral separation methods as indicated where employed:

Example Structure Name NMR LC-MS 24

(4-Fluoro-2-(3-fluoro-3- methylazetidin-1- yl)phenyl)(1H-imidazol-2-yl)methanol 1H NMR (400 MHZ, DMSO-d6) δ ppm 1.56-1.62 (m, 3H),4.01-4.06 (m, 4H), 5.75-5.76 (m, 1H), 5.89-5.91 (m, 1H), 6.28-6.31 (m,1H), 6.53-6.58 (m, 1H), 6.78 (s, 1H), 6.99 (s, 1H), 7.21-7.25 (m, 1H),11.84 (s, 1H). LC-MS (Method A): m/z (ES+), [M + H]+ = 280; acid, HPLCt_(R) = 0.745 min 25

(4-Fluoro-2-(3- methylazetidin-1- yl)phenyl)(1H-imidazol- 2-yl)methanol¹H NMR (300 MHz, DMSO-d6) δ ppm 7.19 (s, 1H), 7.16 (s, 1H), 6.87 (br.s., 2H), 6.45 (d, J = 2.64 Hz, 1H), 6.15 (dd, J = 2.55, 11.99 Hz, 1H),4.06 (d, J = 15.49 Hz, 2H), 3.50 (d, J = 3.59 Hz, 2H), 2.66 (s, 1H),2.58-2.77 (m, 1H), 1.17 (d, J = 6.61 Hz, 3H) LC-MS (Method B): m/z(ES+), [M + H]+ = 262; acid, HPLC t_(R) = 0.48 min 26

(4-Fluoro-2-((S)-3- fluoropyrrolidin-1- yl)phenyl)(1H-imidazol-2-yl)methanol ¹H NMR (300 MHz, DMSO-d6) δ ppm 7.25-7.44 (m, 1H),6.53-7.07 (m, 4H), 5.85-6.11 (m, 2H), 5.17-5.51 (m, 1H), 3.06-3.69 (m,6H), 2.13 (d, J = 5.85 Hz, 2H) LC-MS (Method B): m/z (ES+), [M + H]+ =280; acid, HPLC t_(R) = 0.33 min 27

(4-Fluoro-2-((R)-3- fluoropyrrolidin-1- yl)phenyl)(1H-imidazol-2-yl)methanol ¹H NMR (300 MHz, DMSO-d6) δ ppm 7.24-7.49 (m, 1H),6.54-7.09 (m, 4H), 5.88-6.12 (m, 2H), 5.20-5.50 (m, 1H), 3.33-3.79 (m,2H), 3.14-3.27 (m, 1H), 1.89-2.40 (m, 2H) LC-MS (Method B): m/z (ES+),[M + H]+ = 280; acid, HPLC t_(R) = 0.36 min 28

(2-(3,3- Difluoropyrrolidin-1-yl)- 4-fluorophenyl)(1H-imidazol-2-yl)methanol ¹H NMR (300 MHz, DMSO-d6) δ ppm 7.47 (dd, J =7.08, 8.59 Hz, 1H), 6.61-7.06 (m, 5H), 5.84-6.16 (m, 2H), 3.38 (d, J =6.99 Hz, 4H), 3.07-3.23 (m, 1H), 2.20-2.48 (m, 2H) LC-MS (Method B): m/z(ES+), [M + H]+ = 298; acid, HPLC t_(R) = 0.60 min 29

(4-Fluoro-2-((R)-3- methylpyrrolidin-1- yl)phenyl)(1H-imidazol-2-yl)methanol ¹H NMR (300 MHz, DMSO-d6) δ ppm 1.04 (dd, J = 6.61, 4.15Hz, 3H) 1.28-1.65 (m, 1H) 1.77-2.44 (m, 2H) 2.63-3.02 (m, 1H) 5.67-6.16(m, 2H) 6.45-6.85 (m, 2H) 6.80-7.02 (m, 2H) 7.12-7.48 (m, 1H)11.60-12.55 (m, 1H) LC-MS (Method B): m/z (ES+), [M + H]+ = 276; acid,HPLC t_(R) = 0.63 min 30

(2-(3- Azabicyclo[3.1.0]hexan- 3-yl)-4- fluorophenyl)(1H-imidazol-2-yl)methanol ¹H NMR (300 MHz, DMSO-d6) δ ppm 0.28-0.81 (m, 2H)1.29-1.61 (m, 2H) 2.66-2.92 (m, 1H) 3.29 (s, 5H) 5.61-6.04 (m, 2H)6.63-7.09 (m, 4H) 7.24-7.57 (m, 1H) 11.45-12.00 (m, 1H) LC-MS (MethodB): m/z (ES+), [M + H]+ = 274; acid, HPLC t_(R) = 0.58 min

Example 31.(2-(Bicyclo[3.1.0]hexan-1-yl)-4-fluorophenyl)(1H-imidazol-2-yl)methanol

To the solution of(2-(bicyclo[3.1.0]hexan-1-yl)-4-fluorophenyl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol(43 mg, 0.11 mmol) in DCM (3 mL) was added TFA (0.823 mL, 10.68 mmol).The reaction was stirred at RT for 6 hr. TFA was removed. The residuewas partitioned between EtOAc (30 mL) and sat. NaHCO3 (30 mL). Theorganic layer was collected, washed with water (30 mL), brine (30 mL),dried over MgSO₄, filtered and concentrated. The residue was purifiedvia combiflash (10:1 DCM/MeOH, 24 g column) to give a white solid. 1HNMR (300 MHz, DMSO-d6) δ ppm 0.43-0.93 (m, 2H) 1.13-1.46 (m, 1H)1.53-2.19 (m, 6H) 5.78-6.00 (m, 1H) 6.07-6.25 (m, 1H) 6.62-7.14 (m, 4H)6.93-6.95 (m, 1H) 7.37-7.61 (m, 1H) 11.74-12.03 (m, 1H). LC-MS (MethodB): m/z (ES+), [M+H]+=273; acid, HPLC t_(R)=0.65 min.

A solution of diethylzinc (1.153 mL, 1.15 mmol) in DCM (2.5 mL) wascooled to −40° C. TFA (0.089 mL, 1.15 mmol) was then added dropwise.After an additional 20 min, diiodomethane (0.093 mL, 1.15 mmol) wasadded dropwise. After an additional 20 min,(2-(cyclopent-1-en-1-yl)-4-fluorophenyl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol(Intermediate from Example 5, 80 mg, 0.21 mmol) was added. The reactionwas warmed up to rt, After an additional 30 min, the reaction wasquenched with sat. aqueous NH₄Cl (20 ml) and the layers were separated.The aqueous layer was extracted with DCM (3×20 ml). The combined organiclayers were dried over Na₂SO₄, filtered, and concentrated. The crudeproduct was purified with combiflash. (ethyl acetate in hexanes) toyield product as a yellow oil.

Example 32. (4-Fluoro-2-(oxazol-4-yl)phenyl)(1H-imidazol-2-yl)methanol

Hydrogen chloride/EtOAc (10 mL) was added to(4-fluoro-2-(oxazol-4-yl)phenyl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol(200 mg, 0.51 mmol) under nitrogen. The resulting mixture was stirred atrt for 36 hours. The solvent was removed under reduced pressure. Thecrude product was purified by preparative HPLC (Xselect CSH Fluorophenyl OBD column, 5 μm silica, 19 mm diameter, 100 mm length), usingdecreasingly polar mixtures of water (containing 0.05% Formic acid) andMeCN as eluents. Fractions containing the desired compound wereevaporated to dryness to afford(4-fluoro-2-(oxazol-4-yl)phenyl)(1H-imidazol-2-yl)methanol (100 mg, 75%)as a white solid. ¹H NMR (400 MHz, DMSO) δ ppm 6.05 (1H, s), 6.91 (2H,s), 7.24 (1H, td), 7.46 (1H, dd), 7.71 (1H, dd), 8.26 (1H, s), 8.56 (1H,d), 8.78 (1H, d). LC-MS (Method A): m/z (ES+), [M+H]+=259; base, HPLCt_(R)=1.50 min.

Intermediate E,(4-Fluoro-2-(oxazol-4-yl)phenyl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol

Butyllithium (349 mg, 5.45 mmol) was added dropwise to1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (865 mg, 4.36 mmol) inTHF (10 mL) cooled to −78° C. under nitrogen. The resulting mixture wasstirred at −78° C. for 1 hour. 4-fluoro-2-(oxazol-4-yl)benzaldehyde (417mg, 2.08 mmol) in THF (10 mL) was added. The resulting mixture wasstirred at −78° C. for 30 minutes.

The reaction mixture was quenched with saturated NH₄Cl (10 mL),extracted with EtOAc (2×15 mL), the organic layer was dried over Na₂SO₄,filtered and evaporated to afford white solid.

The crude product was purified by flash C18-flash chromatography,elution gradient 0 to 100% MeCN in water. Pure fractions were evaporatedto dryness to afford(4-fluoro-2-(oxazol-4-yl)phenyl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol(500 mg, 58%) as a white solid. ¹H NMR δ ppm −0.07 (3H, m), 0.83 (15H,m), 1.18 (5H, m), 1.36 (1H, dd), 1.55 (1H, dd), 1.92 (1H, s), 2.00 (4H,s), 3.46 (15H, m), 4.04 (3H, q), 5.32 (12H, m), 5.55 (3H, m), 5.79 (1H,m), 6.19 (4H, m), 6.75 (3H, m), 6.94 (4H, m), 7.25 (11H, m), 7.42 (4H,m), 7.75 (7H, m), 7.90 (2H, d), 8.48 (2H, d), 11.97 (1H, s). LC-MS(Method A): m/z (ES+), [M+H]+=390.10; acid, HPLC t_(R)=1.285 min.

Intermediate D: 4-Fluoro-2-(oxazol-4-yl)benzaldehyde

Manganese(IV) oxide (7201 mg, 82.83 mmol) was added to(4-fluoro-2-(oxazol-4-yl)phenyl)methanol (400 mg, 2.07 mmol) in DCM (10mL) under nitrogen. The resulting mixture was stirred at rt for 24hours. The mixture was filtered through a Celite pad to afford4-fluoro-2-(oxazol-4-yl)benzaldehyde (300 mg, 76%) as a white solid. ¹HNMR δ ppm 0.85 (2H, m), 1.24 (1H, s), 1.57 (9H, d), 5.42 (1H, t), 5.55(2H, s), 5.69 (3H, q), 7.44 (7H, m), 7.66 (12H, m), 7.94 (7H, m), 8.34(1H, t), 8.64 (3H, d), 8.76 (4H, d), 10.18 (1H, d), 10.36 (4H, d). LC-MS(Method A): m/z (ES+), [M+H]+=192.1; acid, HPLC t_(R)=0.998 min.

Intermediate C: (4-Fluoro-2-(oxazol-4-yl)phenyl)methanol

LiAlH₄ (64.3 mg, 1.70 mmol) was added to methyl4-fluoro-2-(oxazol-4-yl)benzoate (250 mg, 1.13 mmol) in THF (5 mL)cooled to −20° C. under nitrogen. The resulting mixture was stirred at−20° C. for 30 minutes. The reaction mixture was quenched with water (1mL), extracted with EtOAc (2×15 mL), the organic layer was dried overNa₂SO₄, filtered and evaporated to afford(4-fluoro-2-(oxazol-4-yl)phenyl)methanol (120 mg, 55.0%) as a whitesolid. LC-MS (Method A): m/z (ES+), [M+H]+=193.95; acid, HPLCt_(R)=0.684 min.

Intermediate B: Methyl 4-fluoro-2-(oxazol-4-yl)benzoate

CO (excess) was added to PdCl₂(dppf) (159 mg, 0.22 mmol), TEA (0.806 mL,5.78 mmol) and 4-(2-bromo-5-fluorophenyl)oxazole (350 mg, 1.45 mmol) inMeOH (5 mL). The resulting mixture was stirred at 130° C. for 20 hours.The solvent was removed under reduced pressure. The crude product waspurified by flash silica chromatography, elution gradient 0 to 10% EtOAcin petroleum ether. Pure fractions were evaporated to dryness to affordmethyl 4-fluoro-2-(oxazol-4-yl)benzoate (251 mg, 78%) as a white solid.¹H NMR δ ppm (400 MHz, CDCl3) 0.88 (5H, dd), 0.98 (1H, m), 1.29 (9H, m),1.46 (5H, m), 1.85 (5H, s), 2.07 (2H, s), 2.55 (7H, s), 2.74 (1H, s),3.13 (5H, s), 3.49 (1H, d), 3.90 (20H, d), 4.15 (2H, q), 7.14 (11H, m),7.31 (3H, td), 7.53 (4H, dd), 7.91 (12H, m), 8.08 (5H, d). LC-MS (MethodA): m/z (ES+), [M+H]+=222.1; acid, HPLC t_(R)=1.024 min.

Intermediate A, 4-(2-bromo-5-fluorophenyl)oxazole

2-Bromo-1-(2-bromo-5-fluorophenyl)ethanone (1 g, 3.38 mmol) was added toformamide (0.152 g, 3.38 mmol) under nitrogen and sealed into amicrowave tube. The reaction was heated to 120° C. for 2 days in themicrowave reactor and cooled to RT. The reaction mixture was dilutedwith EtOAc (25 mL), and washed with saturated brine (15 mL×3). Theorganic layer was dried over Na₂SO₄, filtered and evaporated to affordcrude product. The crude product was purified by flash silicachromatography, elution gradient 0 to 4% EtOAc in petroleum ether. Purefractions were evaporated to dryness to afford4-(2-bromo-5-fluorophenyl)oxazole (0.30 g, 36. %) as a pale yellowsolid.

Example 33. (4-Fluoro-2-(thiazol-4-yl)phenyl)(1H-imidazol-2-yl)methanol

Hydrogen chloride (excess) in EtOAc was added to(4-fluoro-2-(thiazol-4-yl)phenyl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol(100 mg, 0.25 mmol) in EtOAc (6 mL) under nitrogen. The resultingsolution was stirred at rt for 14 hours. The solvent was removed underreduced pressure. The crude product was purified by preparative HPLC(XSelect CSH Prep C18 OBD column, 5 μm silica, 19 mm diameter, 150 mmlength), using decreasingly polar mixtures of water (containing 0.05%formic acid) and MeCN as eluents. Fractions containing the desiredcompound were evaporated to dryness to afford(4-fluoro-2-(thiazol-4-yl)phenyl)(1H-imidazol-2-yl)methanol (29.0 mg,34.2%) as a white solid. ¹H NMR (300 MHz, CD₃OD) δ 6.21-6.22 (m, 1H),7.13-7.25 (m, 3H), 7.37-7.41 (m, 1H), 7.58-7.62 (m, 1H), 7.84 (s, 1H),8.33 (s, 1.5H), 9.11-9.12 (m, 1H). LC-MS (Method A): m/z (ES+),[M+H]+=276.2; acid, HPLC t_(R)=1.207 min.

Intermediate B,(4-fluoro-2-(thiazol-4-yl)phenyl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol

n-Butyllithium (0.386 mL, 0.97 mmol) was added to a stirred solution of1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (191 mg, 0.97 mmol) inTHF (10 mL) at −78° C. under nitrogen. The resulting solution wasstirred at −78° C. for 1 hour. A solution of4-fluoro-2-(thiazol-4-yl)benzaldehyde (100 mg, 0.48 mmol) in THF (3 mL)was added to a stirred solution at −78° C. under nitrogen. The resultingsolution was stirred at −78° C. for 2 hours. The reaction mixture wasquenched with saturated NH4C1 (10 mL), extracted with EtOAc (3×20 mL),the organic layer was dried over Na2SO4, filtered and evaporated toafford yellow oil. The crude product was purified by flash C18-flashchromatography, elution gradient 0 to 70% MeCN in water. Pure fractionswere evaporated to dryness to afford(4-fluoro-2-(thiazol-4-yl)phenyl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol(100 mg, 51%) as a yellow oil. LC-MS (Method A): m/z (ES+),[M+H]+=406.2; acid, HPLC t_(R)=0.721 min.

Intermediate A, 4-fluoro-2-(thiazol-4-yl)benzaldehyde

4-(Tributylstannyl)thiazole (1198 mg, 3.20 mmol) was added to a stirredsolution of 2-bromo-4-fluorobenzaldehyde (500 mg, 2.46 mmol) andbis(triphenylphosphine)palladium(II) chloride (104 mg, 0.15 mmol) in DMF(10 mL) under nitrogen. The resulting solution was stirred at 100° C.for 16 hours. The solution was washed with brine and KF. The aqueouslayer was extracted with EtOAc (2×20 mL). The solvent was removed underreduced pressure to afford crude product. The crude product was purifiedby flash silica chromatography with EtOAc/petroleum ether (1:30). Purefractions were evaporated to dryness to afford4-fluoro-2-(thiazol-4-yl)benzaldehyde (150 mg, 29.4%) as a white solid.LC-MS (Method A): m/z (ES+), [M+H]+=208; acid, HPLC t_(R)=0.802 min.

Example 34. (3-Ethyl-8-fluoroindolizin-5-yl)(1H-imidazol-2-yl)methanol

HCl (0.125 mL, 4.11 mmol) was added to(3-ethyl-8-fluoroindolizin-5-yl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol(160 mg, 0.41 mmol) in EtOAc (5 mL) under nitrogen. The resultingsolution was stirred at rt for 30 hours. The solvent was removed underreduced pressure and redissolved in MeOH (2 ml). The reaction mixturewas neutralized with NH₃.H₂O to pH=7-8. The crude product was purifiedby flash C18-flash chromatography, elution gradient 0 to 100% MeCN inwater. Pure fractions were evaporated to dryness to afford(3-ethyl-8-fluoroindolizin-5-yl)(1H-imidazol-2-yl)methanol (90 mg, 85%)as a off-white solid. ¹H NMR (400 MHz, DMSO) δ ppm 1.29 (3H, t), 2.52(1H, s), 3.20 (1H, dq), 6.42 (4H, m), 6.61 (2H, h), 6.85 (1H, s), 7.10(2H, m), 12.08 (1H, s). LC-MS (Method A): m/z (ES+), [M+H]+=260.1; base,HPLC t_(R)=2.528 min.

Intermediate E,(3-Ethyl-8-fluoroindolizin-5-yl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol

Butyllithium (317 mg, 4.94 mmol) was added portionwise to1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (840 mg, 4.24 mmol) inTHF (5 mL) cooled to −78° C. over a period of 5 minutes under nitrogen.The resulting mixture was stirred at −78° C. for 30 minutes.3-Ethyl-8-fluoroindolizine-5-carbaldehyde (270 mg, 1.41 mmol) in THF (5mL) was added portionwise to the resulting mixture under nitrogen. Theresulting mixture was stirred at −78° C. for 30 minutes. The reactionmixture was quenched with saturated NH₄Cl (5 mL), extracted with EtOAc(2×15 mL), the organic layer was dried over Na₂SO₄, filtered andevaporated to afford(3-ethyl-8-fluoroindolizin-5-yl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol(400 mg, 72.7%) as a colorless oil. ¹HNMR (400 MHz, CDCl₃) δ −0.06 (2H,d), 0.08 (m), 0.71 (qdd), 1.29 (t), 1.48 (t), 2.07 (1H, s), 3.38 (m),4.15 (q), 5.10 (m), 5.81 (dd), 6.11 (dd), 6.63 (s), 6.73 (q), 7.10 (dd).LC-MS (Method A): m/z (ES+), [M+H]+=390.15; acid, HPLC t_(R)=1.585 min.

Intermediate D, 3-Ethyl-8-fluoroindolizine-5-carbaldehyde

Manganese(IV) oxide (4500 mg, 51.76 mmol) was added to compound C (˜400mg) and DCM (2 mL) under nitrogen. The resulting mixture was stirred atrt for 48 hours. The reaction mixture was filtered through celite. Thesolvent was removed under reduced pressure. The crude product waspurified by flash silica chromatography, elution gradient 0 to 1% EtOAcin petroleum ether. Pure fractions were evaporated to dryness to afford3-ethyl-8-fluoroindolizine-5-carbaldehyde (160 mg, 32.3%) as a yellowoil. ¹H NMR (300 MHz, CDCl₃-d) δ 9.93 (s, 1H), 7.47-7.36 (m, 1H), 6.99(d, J=4.4 Hz, 1H), 6.82 (d, J=4.4 Hz, 1H), 6.57-6.44 (m, 1H), 2.99 (q,J=7.6 Hz, 2H), 1.33 (t, J=9.4, 8.4 Hz, 3H). LC-MS (Method A): m/z (ES+),[M+H]+=191.95; acid, HPLC t_(R)=1.004 min.

Intermediate C, (3-Ethyl-8-fluoroindolizin-5-yl)methanol

Lithium aluminum hydride (172 mg, 4.52 mmol) was added slowly to methyl3-ethyl-8-fluoroindolizine-5-carboxylate (500 mg, 2.26 mmol) in THF (8mL) under nitrogen. The resulting mixture was stirred at 0° C. for 1hour. The reaction mixture was quenched with water (5 mL), extractedwith EtOAc (3×15 mL), the organic layer was dried over Na₂SO₄, filteredand evaporated to afford white solid. The crude product was purified byflash C18-flash chromatography, elution gradient 0 to 60% MeCN in water.Pure fractions were evaporated to dryness to afford(3-ethyl-8-fluoroindolizin-5-yl)methanol (260 mg, 59.5%) as a greysolid. ¹H NMR (400 MHz, CDCl₃) δ ppm 6.73-6.63 (m, 2H), 6.44 (dd, J=7.4,5.6 Hz, 1H), 6.24 (dd, J=9.9, 7.4 Hz, 1H), 4.94 (s, 2H), 3.30 (q, J=7.4Hz, 2H), 1.42 (t, J=7.4 Hz, 3H). LC-MS (Method A): m/z (ES+),[M+H]+=194.05; acid, HPLC t_(R)=1.498 min.

Intermediate B, Methyl 3-ethyl-8-fluoroindolizine-5-carboxylate

Copper(I) chloride (0.483 g, 4.88 mmol) was added to methyl5-fluoro-6-(pent-1-yn-1-yl)picolinate (1.08 g, 4.88 mmol) intriethylamine (1.000 mL) and DMA (3.5 mL) under nitrogen. The resultingmixture was stirred at 120° C. for 16 hours. The reaction mixture wasdiluted with EtOAc (25 mL), and washed sequentially with water (15mL×3), saturated brine (15 mL×2), and saturated NH₄Cl (10 mL×2). Theorganic layer was dried over Na₂SO₄, filtered and evaporated to affordcrude product. The crude product was purified by flash silicachromatography, elution gradient 0 to 0% EtOAc in petroleum ether. Thecrude product was purified by flash C18-flash chromatography, elutiongradient 0 to 60% MeCN in water. Pure fractions were evaporated todryness to afford methyl 3-ethyl-8-fluoroindolizine-5-carboxylate (0.550g, 50.9%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.56 (d,J=7.0 Hz, 1H), 7.17 (dd, J=7.8, 5.5 Hz, 2H), 6.87 (d, J=4.2 Hz, 2H),6.75 (d, J=4.1 Hz, 2H), 6.61 (s, 1H), 6.46 (td, J=7.1, 5.1 Hz, 1H),6.41-6.29 (m, 3H), 3.99 (s, 5H), 2.85 (q, J=7.5 Hz, 2H), 2.76-2.66 (m,4H), 1.41 (t, J=7.5 Hz, 3H), 1.31 (t, J=7.4 Hz, 6H). LC-MS (Method A):m/z (ES+), [M+H]+=222.0; acid, HPLC t_(R)=1.072 min.

Intermediate A, Methyl 5-fluoro-6-(pent-1-ynyl)picolinate

Pent-1-yne (0,524 g, 7.69 mmol) and bis(triphenylphosphine)palladium(II)chloride (0.450 g, 0.64 mmol) was added to copper(I) iodide (0.122 g,0.64 mmol), TEA (1.787 mL, 12.82 mmol) and methyl6-bromo-5-fluoropicolinate (1.5 g, 6.41 mmol) in acetonitrile (20 mL)under nitrogen. The resulting mixture was stirred at 80° C. for 3 hours.The solvent was removed under reduced pressure. The crude product waspurified by flash silica chromatography, elution gradient 0 to 10% EtOAcin petroleum ether. Pure fractions were evaporated to dryness to affordmethyl 5-fluoro-6-(pent-1-yn-1-yl)picolinate (1.28 g, 90%) as a orangesolid. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.20-8.06 (m, 2H), 7.52 (dd, J=8.6,8.0 Hz, 2H), 4.14 (q, J=7.1 Hz, 1H), 4.01 (s, 7H), 2.50 (td, J=7.1, 1.0Hz, 4H), 2.07 (s, 1H), 1.71 (h, J=7.3 Hz, 4H), 1.28 (t, J=7.1 Hz, 1H),1.09 (t, J=7.4 Hz, 6H). LC-MS (Method A): m/z (ES+), [M+H]+=222.2; acid,HPLC t_(R)=1.140 min.

Example 35. Pure enantiomer, isomer 1 of(3-Ethyl-8-fluoroindolizin-5-yl)(1H-imidazol-2-yl)methanol

The product was purified by preparative chiral-HPLC on a Chiralpak IAcolumn, eluting isocratically with 10% EtOH in heptane (modified with0.1% DEA) as eluent. The fractions containing the desired compound wereevaporated to dryness to affordP1-(3-ethyl-8-fluoroindolizin-5-yl)(1H-imidazol-2-yl)methanol (60.0 mg,37.5%) as a brown solid (Example 35) andP2-(3-ethyl-8-fluoroindolizin-5-yl)(1H-imidazol-2-yl)methanol (60.0 mg,37.5%) as a brown solid (Example 36). ¹H NMR (400 MHz, DMSO) δ 1.32 (3H,t), 3.22 (1H, dt), 6.21 (1H, s), 6.46 (2H, m), 6.65 (2H, m), 6.77 (2H,s), 7.20 (2H, s), 13.20 (1H, s). m/z (ES+), [M+H]+=260.4; acid, HPLCt_(R)=2.478 min. Analytical chiral HPLC was completed using AmChemteqACI Am-1 column, 0.46×15 cm, 5 μm. The mobile phase A was hexanes (with0.1% DEA) and mobile phase B was ethanol (70/30 mixture A:B). Uv-visdetection at 220 nm. Flow=1.0 ml/min. t_(R)=2.95 min; Purity 99%.

Example 36. Pure enantiomer, isomer 2 of(3-Ethyl-8-fluoroindolizin-5-yl)(1H-imidazol-2-yl)methanol

See example 35. ¹H NMR (300 MHz, DMSO) δ ppm 1.28 (3H, t), 3.19 (2H,qd), 6.44 (4H, m), 6.60 (2H, m), 6.99 (2H, s), 12.21 (1H, s). LC-MS(Method A): m/z (ES+), [M+H]+=260.3; acid, HPLC tR=2.213 min. ChiralHPLC using methods described in Example 35. t_(R)=3.76 min; Purity 99%ee.

Alternative Synthesis to Example 34, 35 and 36.(3-Ethyl-8-fluoroindolizin-5-yl)-(1H-imidazol-2-yl)methanol and PureEnantiomers

2.50 M n-BuLi in THF (11.8 mL, 29.5 mmol) was added to a cooled solutionof 1-(diethoxymethyl)imidazole (5.02 g, 29.5 mmol) in THF (75 mL) at−45° C., and the mixture was stirred for 15 m. The mixture was cooled to−78° C., and a solution of 3-ethyl-8-fluoroindolizine-5-carbaldehyde(2.82 g, 14.8 mmol) in THF (25 mL) was added drop-wise. The mixture wasstirred for 30 m at −78° C. and then warmed to 0° C. for 1 h. Themixture was diluted with 0.1M HCl (50.0 mL) and EtOAc (50.0 mL) at 0° C.The mixture was stirred at 23° C. for 15 m. More EtOAc (50.0 mL) wasadded, and the phases were separated. The organic phase was extractedwith 0.1M HCl (3×50.0 mL), and the combined aqueous phases werecautiously diluted with sat. NaHCO₃ (50.0 mL). The aqueous phase wasextracted with EtOAc (3×200 mL), and the combined organic phases werewashed with brine (200 mL), dried over MgSO₄, filtered and concentratedunder reduced pressure. The compound was identical to material made bythe other descried route, and could be purified by chiral SFCchromatography to provide pure enantiomers as previously described.

Alternate Synthesis Example 34, Intermediate E.3-Ethyl-8-fluoroindolizine-5-carbaldehyde

NMO (8.23 g, 70.3 mmol) was added to a mixture of(3-ethyl-8-fluoroindolizin-5-yl)methanol (6.79 g, 35.1 mmol) and 4 Åmolecular sieves in DCM (100 mL). The mixture was stirred at 23° C. for30 m. The mixture was cooled to 0° C., and TPAP (1.23 g, 3.51 mmol) wasadded in portions. The mixture was warmed to 23° C. for 1 h and filteredthrough a pad of Florisil. The filtrate was concentrated under reducedpressure, and the product was purified by silica gel chromatography (120g cartridge) eluting with hexane and EtOAc (0-30%) to provide the titlecompound as a solid (2.82 g, 42%). ¹H NMR (500 MHz, CDCl₃) δ 9.90 (s,1H), 7.38 (dd, J=7.9, 5.6 Hz, 1H), 6.96 (d, J=4.2 Hz, 1H), 6.79 (d,J=4.2 Hz, 1H), 6.47 (dd, J=9.3, 7.9 Hz, 1H), 2.96 (q, J=7.4 Hz, 2H),1.31 (t, J=7.4 Hz, 3H); LC MS (Method C) m/z (ES+), No ionization.t_(R)=1.76 min.

Alternate Synthesis Example 34, Intermediate D.(3-Ethyl-8-fluoroindolizin-5-yl)methanol

2M LAH in THF (20.5 mL, 40.9 mmol) was added to a cooled solution ofethyl 3-ethyl-8-fluoroindolizine-5-carboxylate (9.63 g, 40.9 mmol) inTHF (90.0 mL) under nitrogen at 0° C. The mixture was stirred at 0° C.for 15 m and then diluted with acetone (10.0 mL) and a sat. solution ofK/Na tartrate (100 mL). Water (100 mL) was added, and the product wasextracted from the aqueous phase with EtOAc (3×200 mL). The combinedorganic phases were washed with brine (200 mL), dried (MgSO₄), filtered,and concentrated under reduced pressure. The product was purified bysilica gel chromatography (120 g cartridge) with hexane and EtOAc(5-60%) to provide the title compound as a solid (6.79 g, 86%). ¹H NMR(500 MHz, CDCl₃) δ 6.68 (d, J=4.1 Hz, 1H), 6.64 (d, J=4.1 Hz, 1H), 6.41(dd, J=7.4, 5.6 Hz, 1H), 6.22 (dd, J=9.8, 7.4 Hz, 1H), 4.91 (d, J=6.2Hz, 2H), 3.27 (q, J=7.4 Hz, 2H), 1.68 (t, J=6.2 Hz, 1H), 1.40 (t, J=7.4Hz, 3H). LC-MS (Method C) m/z (ES+), [M+H]⁺=193.8. HPLC t_(R)=1.51 min.

Alternate Synthesis Example 34, Intermediate C. Ethyl3-ethyl-8-fluoroindolizine-5-carboxylate

A solution of ethyl 5-fluoro-6-pent-1-ynyl-pyridine-2-carboxylate (14.5g, 61.6 mmol) in degassed DMA (193 mL) was added to CuCl (3.05 g, 30.8mmol) under nitrogen. Degassed NEt₃ (27.5 mL, 197 mmol) was added, andthe mixture was stirred at 130° C. for 20 h. The mixture was cooled andfiltered through Celite, washing with EtOAc. The filtrate wasconcentrated under reduced pressure. Water (400 mL) was added to theresidue, and the aqueous phase was extracted with EtOAc (3×500 mL). Thecombined organic phases were washed with brine (500 mL), dried (MgSO₄),filtered, and concentrated under reduced pressure. The product waspurified by silica gel chromatography (220 g cartridge) with hexane andEtOAc (0-20%) to provide the title compound as an oil (9.63 g, 66%). ¹HNMR (500 MHz, CDCl₃) δ 7.14 (dd, J=7.7, 5.5 Hz, 1H), 6.83 (d, J=4.2 Hz,1H), 6.72 (d, J=4.2 Hz, 1H), 6.33 (dd, J=9.7, 7.8 Hz, 1H), 4.43 (q,J=7.1 Hz, 2H), 2.71 (q, J=7.4 Hz, 2H), 1.42 (t, J=7.1 Hz, 3H), 1.28 (t,J=7.4 Hz, 3H). LC-MS (Method C): m/z (ES+), [M+H]⁺=235.9. HPLCt_(R)=2.18 m.

Alternate Synthesis Example 34, Intermediate B. Ethyl5-fluoro-6-pent-1-ynyl-pyridine-2-carboxylate

1-Pentyne (12.1 mL, 123 mmol) was added to a mixture of ethyl6-bromo-5-fluoro-pyridine-2-carboxylate (20.4 g, 82.0 mmol), CuI (2.34g, 12.3 mmol), and PdCl₂(PPh₃)₂ (5.76 g, 8.20 mmol) in degassed toluene(500 mL) at 23° C. under nitrogen. DIPEA (28.6 mL, 164 mmol) was added,and the mixture was stirred in the dark (covered with aluminum foil) for18 h. The mixture was diluted with a sat. solution of NaHCO₃ (400 mL).The aqueous phase was extracted with EtOAc (3×400 mL), and the combinedorganic phases were washed with brine (400 mL), dried (MgSO₄), filtered,and concentrated under reduced pressure. The product was purified bysilica gel chromatography (330 g cartridge) with hexane and EtOAc(0-50%) to provide the title compound as an oil (16.8 g, 87%). ¹H NMR(500 MHz, CDCl₃) δ 8.05 (dd, J=8.6, 4.0 Hz, 1H), 7.54-7.43 (m, 1H), 4.45(q, J=7.1 Hz, 2H), 2.47 (td, J=7.1, 0.7 Hz, 2H), 1.68 (h, J=7.3 Hz, 2H),1.42 (t, J=7.1 Hz, 3H), 1.06 (t, J=7.4 Hz, 3H). LC-MS (Method C): m/z(ES+), [M+H]⁺=235.9. HPLC t_(R)=1.92 m.

Alternate Synthesis Example 34, Intermediate A. Ethyl6-bromo-5-fluoro-pyridine-2-carboxylate

6-Bromo-5-fluoro-pyridine-2-carboxylic acid (24.0 g, 109 mmol) wasdissolved in a mixture of EtOH (400 mL) and conc. H₂SO₄ (17.5 mL, 328mmol). The mixture was heated at 90° C. for 2.5 h. After cooling to 0°C., a solution of 3.50 M NaOH (90.0 mL, 315 mmol) was slowly added withvigorous stirring (pH adjusted to approx. 4), followed by a sat.solution of NaHCO₃ until pH was approx. 8. The slurry was filteredthrough a pad of Celite, and the filtrate was concentrated under reducedpressure. The residue was suspended in cold water (300 mL) and stirredat 0° C. for 5 m. The mixture was filtered, washing with water, and thesolid was dried under vacuum to provide the title compound as a solid(20.4 g, 75%). ¹H NMR (500 MHz, CDCl₃) δ 8.12 (dd, J=8.3, 3.6 Hz, 1H),7.53 (dd, J=8.3, 7.0 Hz, 1H), 4.47 (q, J=7.1 Hz, 2H), 1.43 (t, J=7.1 Hz,3H). LC-MS (Method C): m/z (ES+), [M+H]⁺=247.8. HPLC t_(R)=1.74 m.

Example 37. (8-Fluoro-3-methylindolizin-5-yl)(1H-imidazol-2-yl)methanol

Made in analogous fashion to Example 34. ¹H NMR (300 MHz, DMSO-d6) δ ppm12.08 (s, 1H), 7.08 (s, 1H), 6.86 (s, 1H), 6.53 (t, J=3.7 Hz, 2H),6.47-6.35 (m, 2H), 6.30 (d, J=7.1 Hz, 1H), 2.71 (s, 3H). LC-MS (MethodA): m/z (ES+), [M+H]+=246.2; alkali, HPLC t_(R)=1.357 min.

Example 38.(8-Fluoro-3-isopropylindolizin-5-yl)(1H-imidazol-2-yl)methanol

Example 38 was made by analogous fashion to Example 34. ¹H NMR (300 MHz,DMSO-d6) δ ppm 12.12 (s, 1H), 7.10 (s, 1H), 6.86 (s, 1H), 6.74 (d, J=4.2Hz, 1H), 6.63 (d, J=4.2 Hz, 1H), 6.56-6.26 (m, 4H), 3.77 (p, J=6.6 Hz,1H), 1.35-1.21 (m, 6H). LC-MS (Method A modified to basic conditions):m/z (ES+), [M+H]+=274.2; alkali, HPLC t_(R)=1.559 min.

Example 39.(3-Cyclopropyl-8-fluoroindolizin-5-yl)(1H-imidazol-2-yl)methanol

Example 38 was made by analogous fashion to Example 34. The followingmodifications were made for the final deprotection step.Perchlorostannane (130 mg, 0.50 mmol) was added to(3-cyclopropyl-8-fluoroindolizin-5-yl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol(200 mg, 0.50 mmol) in DCM (4 mL) under nitrogen. The resulting solutionwas stirred at rt for 30 hours. The solvent was removed under reducedpressure and redissolved in MeOH (2 ml). The reaction mixture wasneutralized with NH₃.H₂O to pH=7-8. The crude product was purified bypreparative HPLC (XSelect CSH Prep C18 OBD column, 5μ silica, 19 mmdiameter, 100 mm length), using decreasingly polar mixtures of water(containing 0.05% NH₄HCO₃) and MeCN as eluents. Fractions containing thedesired compound were evaporated to dryness to afford(3-cyclopropyl-8-fluoroindolizin-5-yl)(1H-imidazol-2-yl)methanol (10.00mg, 7.40%) as a off-white solid. ¹H NMR (400 MHz, MeOD) □ ppm 0.78 (1H,tt), 0.91 (1H, tt), 1.03 (2H, s), 1.31 (1H, s), 2.42 (1H, ddd), 5.11(5H, s), 6.27 (2H, m), 6.54 (2H, m), 7.08 (2H, s), 7.37 (1H, s). LC-MS(Method A, modified to basic conditions): m/z (ES+), [M+H]+=272.0; base,HPLC t_(R)=1.511 min.

Example 40. (3-Ethyl-7-fluorobenzofuran-4-yl)(1H-imidazol-2-yl)methanol

Hydrogen chloride in dioxane (73.0 mL, 291.91 mmol) was added dropwiseto(3-ethyl-7-fluorobenzofuran-4-yl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol(5.7 g, 14.60 mmol) in 1,4-dioxane (20 mL) in ice bath under nitrogen.The temperature was increased to room temperature naturally. Theresulting solution was stirred at 40° C. overnight. The solvent wasremoved under reduced pressure to give a crude product. The crudeproduct was basified with 7M NH₃ in MeOH, and purified by flashC18-flash chromatography, elution gradient 0 to 30% MeCN in water. Purefractions were evaporated to dryness to afford(3-ethyl-7-fluorobenzofuran-4-yl)(1H-imidazol-2-yl)methanol (2.500 g,65.8%) as a white solid. ¹HNMR (300 MHz, DMSO-d6) □ ppm 1.11-1.29 (3H,t, J 7.4), 2.63-2.98 (2H, m), 6.18-6.32 (2H, m), 6.84-6.93 (2H, s),7.12-7.22 (1H, dd, J 10.7, 8.5), 7.23-7.33 (1H, dd, J 8.5, 4.7),7.77-7.84 (1H, s), 12.01-12.13 (1H, s). LC-MS (Method A): m/z (ES+),[M+H]+=261.4; acid, HPLC t_(R)=1.539 min.

Intermediate D,(3-Ethyl-7-fluorobenzofuran-4-yl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol

Butyllithium (13.05 mL, 32.62 mmol) was added dropwise to1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (7.06 g, 35.59 mmol),in THF (150 mL) cooled to −70° C. over a period of 5 minutes undernitrogen. 3-ethyl-7-fluorobenzofuran-4-carbaldehyde (5.7 g, 29.66 mmol)in THF (15 mL) was added dropwise after the reaction had been stirredfor 1.5 hour at −70° C. The reaction was incomplete so the mixture wasleft to stir for 1 hour at −70° C. The reaction mixture was quenchedwith saturated NH₄Cl (200 mL), extracted with EtOAc (3×200 mL), theorganic layer was dried over Na₂SO₄, filtered and evaporated to affordyellow oil. The crude product was purified by flash C18-flashchromatography, elution gradient 0 to 50% MeCN in water. Pure fractionswere evaporated to dryness to afford(3-ethyl-7-fluorobenzofuran-4-yl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol(5.72 g, 49.4%) as a white solid. ¹H NMR (300 MHz, DMSO-d6) □ ppm−0.07-−0.01 (9H, s), 0.69-0.94 (2H, dddd, J=35.8, 13.8, 9.7, 6.9),1.06-1.18 (3H, t, J=7.4), 2.22-2.42 (1H, m), 2.52-2.67 (1H, m),3.36-3.56 (2H, ddq, J=9.5, 6.7, 3.0), 5.26-5.36 (1H, d, J=10.7),5.60-5.71 (1H, d, J=10.7), 6.18-6.25 (1H, d, J=6.0), 6.29-6.38 (1H, d,J=6.0), 6.69-6.76 (1H, d, J=1.1), 7.12-7.22 (1H, dd, J=10.8, 8.5),7.27-7.38 (2H, m), 7.73-7.79 (1H, s). LC-MS (Method A): m/z (ES+),[M+H]+=391.4; acid, HPLC t_(R)=2.323 min.

Intermediate C, 3-Ethyl-7-fluorobenzofuran-4-carbaldehyde

DMF (0.637 mL, 8.23 mmol) was added slowly to4-bromo-3-ethyl-7-fluorobenzofuran (1 g, 4.11 mmol) and butyllithium(2.468 mL, 6.17 mmol) in THF (20 mL) at −78° C. over a period of 1 hourunder nitrogen. The resulting solution was stirred at −78° C. for 1hour. The reaction mixture was quenched with saturated NH₄Cl (20 mL),extracted with EtOAc (2×25 mL), the organic layer was dried over Na₂SO₄,filtered and evaporated to afford white solid. The crude product waspurified by flash silica chromatography, elution gradient 0 to 20% EtOAcin petroleum ether. Pure fractions were evaporated to dryness to afford3-ethyl-7-fluorobenzofuran-4-carbaldehyde (0.570 g, 72.1%) as a whitesolid. LC-MS (Method A): m/z (ES+), [M+H]+=193; acid, HPLC t_(R)=1.652min.

Intermediate B, 4-Bromo-3-ethyl-7-fluorobenzofuran

Polyphosphoric acid (11.76 g, 49.03 mmol) was added to1-(5-bromo-2-fluorophenoxy)butan-2-one (6.4 g, 24.51 mmol) in toluene(50 mL) under nitrogen. The resulting mixture was stirred at 120° C. for14 hours. The reaction mixture was poured into water (50 mL), extractedwith EtOAc (2×75 mL), the organic layer was dried over Na₂SO₄, filteredand evaporated to afford white liquid. The crude product was purified byflash silica chromatography, elution gradient 0 to 1% EtOAc in petroleumether. Pure fractions were evaporated to dryness to afford4-bromo-3-ethyl-7-fluorobenzofuran (2.20 g, 36.9%) as a white solid useas is without further purification.

Intermediate A, 1-(5-bromo-2-fluorophenoxy)butan-2-one

1-Bromobutan-2-one (26.1 g, 172.78 mmol) was added to5-bromo-2-fluorophenol (30 g, 157.07 mmol) and K₂CO₃ (54.3 g, 392.67mmol) in MeCN (500 mL) at 25° C. over a period of 0.5 hour undernitrogen. The resulting solution was stirred at 60° C. for 3 hours. Thesolvent was removed under reduced pressure. The crude product waspurified by flash silica chromatography, elution gradient 0 to 10% EtOAcin petroleum ether. Pure fractions were evaporated to dryness to afford1-(5-bromo-2-fluorophenoxy)butan-2-one (31.0 g, 76%) as a white solid.¹H NMR (300 MHz, Methanol-d4) δ ppm 1.02-1.14 (t, J=7.3 Hz, 3H),2.54-2.67 (q, J=7.3 Hz, 2H), 4.78-4.85 (s, 2H), 7.00-7.13 (m, 2H),7.14-7.22 (dd, J=7.6, 2.0 Hz, 1H). LC-MS (Method A): m/z (ES+),[M+H]+=unknown; acid, HPLC t_(R)=1.574 min.

Example 41. Pure enantiomer, Peak 2,(R)-(3-Ethyl-7-fluorobenzofuran-4-yl)(1H-imidazol-2-yl)methanol

Example 40 was purified by preparative chiral-HPLC on a CHIRALPAK AD-HSFC, 5×25 cm, 5 μm with 30% MeOH in other solvent (modified with 0.1%IPAmine) as eluent. The fractions containing the desired compound wereevaporated to dryness to afford(3-ethyl-7-fluorobenzofuran-4-yl)(1H-imidazol-2-yl)methanol (0.850 g,38.2%) as a white solid. Mobile Phase A:CO₂: Mobile Phase B: MeOH (0.1%IPAmine) (70:30 ratio). Flow rate: 170 mL/min; 254 nm; Peak 2 tR=5.66min ¹HNMR (300 MHz, Methanol-d4) δ ppm 1.20-1.37 (3H, t, J 7.4),2.62-2.86 (2H, m), 6.31-6.38 (1H, s), 6.95-7.08 (3H, m), 7.08-7.18 (1H,dd, J 8.4, 4.5), 7.55-7.62 (1H, t, J 1.4). LC-MS (Method A): m/z (ES+),[M+H]+=260.95; acid, HPLC t_(R)=1.263 min.

Example 42. Pure Enantiomer, Peak 1,(S)-(3-Ethyl-7-fluorobenzofuran-4-yl)(1H-imidazol-2-yl)methanol

Example 40 was purified by preparative chiral-HPLC on a CHIRALPAK AD-HSFC, 5×25 cm, 5 μm with 30% MeOH in other solvent (modified with 0.1%IPAmine) as eluent. The fractions containing the desired compound wereevaporated to dryness to afford(3-ethyl-7-fluorobenzofuran-4-yl)(1H-imidazol-2-yl)methanol (0.850 g,38.2%) as a white solid. Mobile Phase A:CO₂: Mobile Phase B: MeOH (0.1%IPAmine) (70:30 ratio). Flow rate: 170 mL/min; 254 nm; Peak 1, tR=:4.29min. Absolute stereochemistry established by X-ray crystal structure inPar2 protein. ¹HNMR (300 MHz, DMSO-d6) δ ppm 1.17-1.29 (3H, t, J 7.4),2.64-2.98 (2H, m), 6.18-6.25 (1H, s), 6.85-6.92 (2H, s), 7.10-7.34 (2H,m), 7.77-7.83 (1H, s), 8.11-8.17 (1H, s), 11.81-12.88 (1H, s). LC-MS(Method A): m/z (ES+), [M+H]+=260.95; acid, HPLC t_(R)=1.263 min.

Example 43.(3-Cyclopropyl-7-fluorobenzofuran-4-yl)(1H-imidazol-2-yl)methanol

Example 43 was prepared in analogous fashion to example 40, utilizing2-bromo-1-cyclopropylethanone. ¹HNMR (400 MHz, DMSO-d6) δ ppm 0.55 (1H,q), 0.64 (1H, m), 0.78 (2H, m), 1.98 (1H, s), 6.79 (1H, d), 7.11 (1H,m), 7.28 (2H, m), 7.60 (2H, s), 7.93 (1H, d), 14.23 (2H, s). LC-MS(Method A): m/z (ES+), [M+H]+=273.1; base, HPLC t_(R)=2.552 min.

Example 44. Pure Enantiomer, Isomer 1,(3-Cyclopropyl-7-fluorobenzofuran-4-yl)(1H-imidazol-2-yl)methanol

Example 43 was purified by preparative chiral-HPLC on a Chiralpak IAcolumn, eluting isocratically with 10% IPA hexane (modified with 0.1%DEA) as eluent. The fractions containing the desired compound wereevaporated to dryness to affordP1-(3-cyclopropyl-7-fluorobenzofuran-4-yl)(1H-imidazol-2-yl)methanol(40.0 mg, 40.0%, Example 44) andP2-(3-cyclopropyl-7-fluorobenzofuran-4-yl)(1H-imidazol-2-yl)methanol(40.0 mg, 40.0%, Example 45) as a off-white solid. ¹HNMR (400 MHz,DMSO-d6) δ ppm 0.51 (1H, q), 0.81 (3H, m), 2.16 (1 H, p), 6.26 (1H, d),6.62 (1H, d), 6.76 (1H, s), 7.00 (1H, s), 7.18 (1H, dd), 7.33 (1H, dd),7.79 (1H, d), 11.96 (1H, s). LC-MS (Method A, modified to basicconditions): m/z (ES+), [M+H]+=273.2; base, HPLC t_(R)=1.814 min.Analytical chiral HPLC methods:ODH column, (0.46×10 cm, 5 μM), mobilephase A: Hexanes, mobile phase B: ethanol (90:10 ratio), detection at254 nm. t_(R)=3.75.

Example 45. Pure Enantiomer, Isomer 2,(3-Cyclopropyl-7-fluorobenzofuran-4-yl)(1H-imidazol-2-yl)methanol

Example 45 was purified by preparative chiral-HPLC on a Chiralpak IAcolumn, eluting isocratically with 10% IPA hexane (modified with 0.1%DEA) as eluent. The fractions containing the desired compound wereevaporated to dryness to affordP1-(3-cyclopropyl-7-fluorobenzofuran-4-yl)(1H-imidazol-2-yl)methanol(40.0 mg, 40.0%, Example 45) andP2-(3-cyclopropyl-7-fluorobenzofuran-4-yl)(1H-imidazol-2-yl)methanol(40.0 mg, 40.0%, Example 45) as a off-white solid. ¹HNMR (400 MHz,DMSO-d6) δ ppm 0.53 (1H, m), 0.80 (3H, m), 2.15 (1H, q), 6.26 (1H, d),6.62 (1H, d), 6.76 (1H, s), 7.00 (1H, s), 7.18 (1H, dd), 7.33 (1H, dd),7.79 (1H, d), 11.96 (1H, s). LC-MS (Method A, modified to basicconditions): m/z (ES+), [M+H]+=273.2; base, HPLC t_(R)=1.903 min.Analytical chiral HPLC methods: ODH column, (0.46×10 cm, 5 μM), mobilephase A: Hexanes, mobile phase B: ethanol (90:10 ratio), detection at254 nm. t_(R)=5.43.

Example 46,(7-Fluoro-3-(2,2,2-trifluoroethyl)benzofuran-4-yl)(1H-imidazol-2-yl)methanol

(7-Fluoro-3-(2,2,2-trifluoroethyl)benzofuran-4-yl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol(100 mg, 0.22 mmol) was added EtOAc/HCl (2 mL) at rt under nitrogen. Theresulting solution was stirred at rt for 16 hours. The solvent wasremoved under reduced pressure. The crude product was purified bypreparative HPLC (XSelect CSH Prep C18 OBD column, 5 μm silica, 19 mmdiameter, 150 mm length), using decreasingly polar mixtures of water(containing 0.1% Formic acid) and MeCN as eluents. Fractions containingthe desired compound were evaporated to dryness to afford(7-fluoro-3-(2,2,2-trifluoroethyl)benzofuran-4-yl)(1H-imidazol-2-yl)methanol(20.00 mg, 24.30%) as a white solid. ¹H NMR (400 MHz, Methanol-d4) δ3.43-3.61 (1H, m), 3.91 (1H, dtd), 6.28 (1H, s), 7.06-7.18 (4H, m),7.85-7.93 (1H, m), 8.46 (1H, s). LC-MS (Method A): m/z (ES+),[M·+]=315.2; acid, HPLC t_(R)=2.21 min. F NMR (400 MHz, Methanol-d4, 23°C.) δ −140.3 (1F), −67.2 (3F).

Intermediate H,(7-Fluoro-3-(2,2,2-trifluoroethyl)benzofuran-4-yl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol

BuLi (0.471 mL, 1.18 mmol) was added dropwise to1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (234 mg, 1.18 mmol) inTHF (5 mL) cooled to −78° C. under nitrogen. The resulting solution wasstirred at −78° C. for 1 hour.7-fluoro-3-(2,2,2-trifluoroethyl)benzofuran-4-carbaldehyde (145 mg, 0.59mmol) in THF (1 mL) was added dropwise. The resulting solution wasstirred at −78° C. for another 1 hour. The reaction mixture was quenchedwith saturated NH₄Cl (10 mL), extracted with EtOAc (3×5 mL), the organiclayer was dried over Na₂SO₄, filtered and evaporated to afford colorlessresidue. The crude product was purified by flash C18-flashchromatography, elution gradient 0 to 100% MeCN in water. Pure fractionswere evaporated to dryness to afford(7-fluoro-3-(2,2,2-trifluoroethyl)benzofuran-4-yl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol(138 mg, 52.7%) as a colorless gum. LC-MS (Method A): m/z (ES+),[M+H]+=445.2; acid, HPLC t_(R)=0.82 min.

Intermediate G,7-Fluoro-3-(2,2,2-trifluoroethyl)benzofuran-4-carbaldehyde

Manganese dioxide (10.51 mg, 0.12 mmol) was added to a stirred mixtureof (7-fluoro-3-(2,2,2-trifluoroethyl)benzofuran-4-yl)methanol (30 mg,0.12 mmol) in DCM (5 mL) under nitrogen. The resulting mixture wasstirred at rt for 16 hours. The reaction mixture was filtered throughcelite. The solvent was removed under reduced pressure. This resulted in7-fluoro-3-(2,2,2-trifluoroethyl)benzofuran-4-carbaldehyde (20.00 mg,67.2%) as a white solid. ¹H NMR (300 MHz, CDCl₃) δ ppm 4.14 (2H, qd),7.27 (1H, dd), 7.75-7.88 (2H, m), 10.08 (1H, s).

Intermediate F,(7-Fluoro-3-(2,2,2-trifluoroethyl)benzofuran-4-yl)methanol

LiAlH₄ (5.50 mg, 0.14 mmol) was added to methyl7-fluoro-3-(2,2,2-trifluoroethyl)benzofuran-4-carboxylate (40 mg, 0.14mmol) in THF (5 mL) cooled to −20° C. under nitrogen. The resultingsolution was warmed to 0° C. and stirred at 0° C. for 30 minutes. Thereaction mixture was quenched with saturated NH₄Cl (5 mL), extractedwith EtOAc (2×5 mL), the organic layer was dried over Na₂SO₄, filteredand evaporated to afford(7-fluoro-3-(2,2,2-trifluoroethyl)benzofuran-4-yl)methanol (35.0 mg,97%) as a light yellow solid.

Intermediate E, Methyl7-fluoro-3-(2,2,2-trifluoroethyl)benzofuran-4-carboxylate

4-Bromo-7-fluoro-3-(2,2,2-trifluoroethyl)benzofuran (100 mg, 0.34 mmol),PdCl₂(dppf)-CH₂Cl₂Adduct (275 mg, 0.34 mmol) and Et₃N (0.047 mL, 0.34mmol) in MeOH (10 mL) were stirred under an atmosphere of carbonmonoxide at 40 atm and 130° C. for 16 hours. The solvent was removedunder reduced pressure. The crude product was purified by flash silicachromatography, elution gradient 0 to 1% EtOAc in petroleum ether. Purefractions were evaporated to dryness to afford methyl7-fluoro-3-(2,2,2-trifluoroethyl)benzofuran-4-carboxylate (40.0 mg,43.0%) as a white solid. ¹H NMR (300 MHz, CDCl₃) δ ppm 3.88-4.06 (5H,m), 7.11 (1H, dd), 7.77 (1H, s), 7.89 (1H, dd).

Intermediate D, 4-Bromo-7-fluoro-3-(2,2,2-trifluoroethyl)benzofuran

Trimethyl(trifluoromethyl)silane (942 mg, 6.62 mmol) was added to((thiophene-2-carbonyl)oxy)copper (211 mg, 1.10 mmol), potassiumfluoride (385 mg, 6.62 mmol) and4-bromo-3-(bromomethyl)-7-fluorobenzofuran (340 mg, 1.10 mmol) in THF(10 mL) under nitrogen. The resulting mixture was stirred at 75° C. for4 hours. The reaction mixture was quenched with water (10 mL), extractedwith EtOAc (2×20 mL), the organic layer was dried over Na₂SO₄, filteredand evaporated to afford orange residue. The crude product was purifiedby flash silica chromatography, elution gradient 0 to 1% EtOAc inpetroleum ether. Pure fractions were evaporated to dryness to afford4-bromo-7-fluoro-3-(2,2,2-trifluoroethyl)benzofuran (120 mg, 36.6%) as acolorless liquid. ¹HNMR (300 MHz, CDCl₃) δ ppm 4.13 (2H, q), 6.98 (1H,dd), 7.36 (1H, dd), 7.72 (1H, q).

Intermediate C, 4-Bromo-3-(bromomethyl)-7-fluorobenzofuran

NBS (31.1 mg, 0.17 mmol) was added to4-bromo-7-fluoro-3-methylbenzofuran (40 mg, 0.17 mmol) and benzoicperoxyanhydride (42.3 mg, 0.17 mmol) in CCl₄ (2 mL) at 25° C. undernitrogen. The resulting mixture was stirred at 85° C. for 16 hours. Theresidue was purified by preparative TLC (petroleum ether:EtOAc=50:1), toafford 4-bromo-3-(bromomethyl)-7-fluorobenzofuran (20.00 mg, 37.2%) as ayellow solid.

Intermediate B, 4-Bromo-7-fluoro-3-methylbenzofuran

Polyphosphoric acid (5 mL, 14.17 mmol) was added to1-(5-bromo-2-fluorophenoxy)propan-2-one (3.5 g, 14.17 mmol) at 25° C.under nitrogen. The resulting solution was stirred at 110° C. for 16hours. The reaction mixture was quenched with water (25 mL), extractedwith EtOAc (3×100 mL), the organic layer was dried over Na2SO4, filteredand evaporated to afford dark residue. The crude product was purified byflash silica chromatography, elution gradient 0 to 5% EtOAc in petroleumether. Pure fractions were evaporated to dryness to afford4-bromo-7-fluoro-3-methylbenzofuran (1.370 g, 42.2%) as a white solid.¹HNMR (400 MHz, CDCl₃) δ ppm 2.45 (3H, d), 6.91 (1H, dd), 7.29 (1H, dd),7.48 (1H, q).

Intermediate A, 1-(5-Bromo-2-fluorophenoxy)propan-2-one

1-Bromopropan-2-one (8.61 g, 62.83 mmol) was added dropwise to5-bromo-2-fluorophenol (10 g, 52.36 mmol) and K₂CO₃ (10.85 g, 78.53mmol) in acetone (200 mL) at 60° C. over a period of 30 minutes undernitrogen. The resulting mixture was stirred at 60° C. for 2 hours. Thereaction mixture was filtered through celite. The reaction mixture wasdiluted with EtOAc (300 mL), and washed with water (200 mL×3). Theorganic layer was dried over Na₂SO₄, filtered and evaporated to affordcrude product. The crude product was purified by flash silicachromatography, elution gradient 0 to 10% EtOAc in petroleum ether. Purefractions were evaporated to dryness to afford1-(5-bromo-2-fluorophenoxy)propan-2-one (10.90 g, 84%) as a white solid.¹H NMR (400 MHz, DMSO-d6) δ 7.34-7.09 (m, 3H), 5.00 (s, 2H), 2.16 (s,3H).

Example 47. Pure Enantiomer, Isomer 1,(7-fluoro-3-(2,2,2-trifluoroethyl)benzofuran-4-yl)(1H-imidazol-2-yl)methanol

The crude product(7-fluoro-3-(2,2,2-trifluoroethyl)benzofuran-4-yl)(1H-imidazol-2-yl)methanol(200 mg, 0.64 mmol) was purified by preparative chiral-HPLC on aChiralpak IB column, eluting isocratically with 30% EtOH in heptane(modified with diethylamine) as eluent. The fractions containing thedesired compound were evaporated to dryness to afford(7-fluoro-3-(2,2,2-trifluoroethyl)benzofuran-4-yl)(1H-imidazol-2-yl)methanol(50 mg, 25%) Peak 1 as a white solid. and(7-fluoro-3-(2,2,2-trifluoroethyl)benzofuran-4-yl)(1H-imidazol-2-yl)methanol(40 mg, 20%) Peak 2 as a white solid. ¹HNMR (400 MHz, DMSO-d6) δ ppm3.98-4.26 (2H, m), 6.19 (1H, d), 6.48 (1H, d), 6.80 (1H, s), 7.02 (1H,s), 7.21-7.39 (2H, m), 8.09 (1H, s), 11.99 (1H, s). LC-MS (Method A):m/z (ES+), [M+H]+=315.3; acid, HPLC t_(R)=1.44 min. Chiral analyticalHPLC. Chiral Amylose-SA column, 0.46×15 cm, 5 μM, Mobile Phase A hexanes(0.2% IPA), Mobile Phase B ethanol (70:30). Flow rate 1.0 mL/min, UV-visdetection 254 nm. t_(R)=2.71 min.

Example 48, Pure Enantiomer, Isomer 2,(7-fluoro-3-(2,2,2-trifluoroethyl)benzofuran-4-yl)(1H-imidazol-2-yl)methanol

The crude product(7-fluoro-3-(2,2,2-trifluoroethyl)benzofuran-4-yl)(1H-imidazol-2-yl)methanol(200 mg, 0.64 mmol) was purified by preparative chiral-HPLC on aChiralpak IB column, eluting isocratically with 30% EtOH in heptane(modified with diethylamine) as eluent. The fractions containing thedesired compound were evaporated to dryness to afford(7-fluoro-3-(2,2,2-trifluoroethyl)benzofuran-4-yl)(1H-imidazol-2-yl)methanol(50 mg, 25%) Peak 1 as a white solid. and(7-fluoro-3-(2,2,2-trifluoroethyl)benzofuran-4-yl)(1H-imidazol-2-yl)methanol(40 mg, 20%) Peak 2 as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ ppm4.03-4.21 (2H, m), 6.19 (1H, d), 6.48 (1H, d), 6.80 (1H, s), 7.02 (1H,s), 7.21-7.39 (2H, m), 8.09 (1H, s), 11.99 (1H, s).LC-MS (Method A): m/z(ES+), [M+H]+=acid, HPLC t_(R)=1.99 min. Chiral analytical HPLC. ChiralAmylose-SA column, 0.46×15 cm, 5 μm, Mobile Phase A hexanes (0.2% IPA),Mobile Phase B ethanol (70:30). Flow rate 1.0 mL/min, UV-vis detection254 nm. t_(R)=4.44 min.

Example 49,(3-Ethyl-7-fluorobenzo[b]thiophen-4-yl)(1H-imidazol-2-yl)methanol

Example 49 was made in analogous fashion to Example 40 using5-bromo-2-fluorobenzenethiol and 1-bromobutan-2-one.). LC-MS (Method A):m/z (ES+), [M+H]+=277; acid, HPLC t_(R)=1.487 min.

Example 50. Pure Enantiomer, Isomer 1,(3-Ethyl-7-fluorobenzo[b]thiophen-4-yl)(1H-imidazol-2-yl)methanol

Example 49 was purified by preparative chiral-HPLC on a Chiralpak IAcolumn, eluting isocratically with 6% EtOH in heptane (modified withTEAA) as eluent. The fractions containing the desired compound wereevaporated to dryness to afford(3-ethyl-7-fluorobenzo[b]thiophen-4-yl)(1H-imidazol-2-yl)methanol (44.0mg, 32.4%) as a white solid (Example 51, peak 1). ¹H NMR (400 MHz, DMSO)δ 1.29-1.33 (m, 3H), 3.06-3.22 (m, 2H), 6.27-6.28 (m, 1H), 6.52-6.53 (m,1H), 6.89 (s, 2H), 7.19-7.23 (m, 1H), 7.49-7.52 (m, 2H), 11.97 (s, 1H).LC-MS (Method A): m/z (ES+), [M+H]+=277; acid, HPLC t_(R)=1.484 min.Chiral analytical HPLC. ODH column, 0.46×10 cm, 5 μm, Mobile Phase Ahexanes (0.1% DEA), Mobile Phase B ethanol (85:15). Flow rate 1.0mL/min, UV-vis detection 254 nm. t_(R)=2.59 min.

Example 51. Pure Enantiomer, Isomer 2,(3-Ethyl-7-fluorobenzo[b]thiophen-4-yl)(1H-imidazol-2-yl)methanol

Example 49 was purified by preparative chiral-HPLC on a Chiralpak IAcolumn, eluting isocratically with 6% EtOH in heptane (modified withTEAA) as eluent. The fractions containing the desired compound wereevaporated to dryness to afford(3-ethyl-7-fluorobenzo[b]thiophen-4-yl)(1H-imidazol-2-yl)methanol (44.0mg, 32.4%) as a white solid (Example 51, peak 2). ¹H NMR (400 MHz, DMSO)δ ppm 1.30-1.33 (m, 3H), 3.09-3.24 (m, 2H), 6.27-6.28 (m, 1H), 6.52-6.53(m, 1H), 6.89 (s, 2H), 7.19-7.23 (m, 1H), 7.49-7.52 (m, 2H), 11.97 (s,1H). LC-MS (Method A): m/z (ES+), [M+H]+=277; acid, HPLC t_(R)=1.487min. Chiral analytical HPLC. ODH column, 0.46×10 cm, 5 μm, Mobile PhaseA hexanes (0.1% DEA), Mobile Phase B ethanol (85:15). Flow rate 1.0mL/min, UV-vis detection 254 nm. t_(R)=3.96 min.

Example 52. (7-Fluoro-3-methylbenzofuran-4-yl)(1H-imidazol-2-yl)methanol

Example 52 was made in analogous fashion to example 40, using1-bromopropan-2-one. ¹H NMR (400 MHz, DMSO-d6) δ ppm 2.26 (s, 3H),6.27-6.24 (s, 2H), 6.84-6.95 (m, 2H), 7.13-7.18 (m, 1H), 7.25-7.28 (m,1H), 7.80 (s, 1H), 8.21 (s, 0.5H).

Example 53. (4-Fluorodibenzo[b,d]furan-1-yl)(1H-imidazol-2-yl)methanol

HCl/EtOAc (10 mL) was added to(4-fluorodibenzo[b,d]furan-1-yl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol(300 mg, 0.73 mmol). The resulting mixture was stirred at rt for 12hours. The solvent was removed under reduced pressure. The crude productwas purified by preparative HPLC (XSelect CSH Prep C18 OBD column, 5 μmsilica, 19 mm diameter, 150 mm length), using decreasingly polarmixtures of water (containing 0.1% Formic acid) and MeCN as eluents.Fractions containing the desired compound were evaporated to dryness toafford (4-fluorodibenzo[b,d]furan-1-yl)(1H-imidazol-2-yl)methanol (130mg, 50.7%) as a white solid. ¹H NMR (300 MHz, Methanol-d4) δ ppm 6.55(s, 1H), 7.16 (d, 2H), 7.34 (dd, 3H), 7.54 (t, 1H), 7.67 (d, 1H), 7.98(d, 1H), 8.22 (s, 1.5H). LC-MS (method A): m/z (ES+), [M+H]+=283; base,HPLC t_(R)=1.46 min.

Intermediate E,(4-Fluorodibenzo[b,d]furan-1-yl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol

BuLi (747 μL, 1.87 mmol) was added dropwise to1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (370 mg, 1.87 mmol) inTHF (10 mL) at −78° C. over a period of 0.5 hour under nitrogen.4-fluorodibenzo[b,d]furan-1-carbaldehyde (200 mg, 0.93 mmol) in (1 mL)was added The resulting mixture was stirred at −78° C. for 1 hour. Thereaction mixture was quenched with water (10 mL), extracted with EtOAc(3×10 mL), the organic layer was evaporated. The crude product waspurified by flash C18-flash chromatography, elution gradient 0 to 100%water in MeCN. Pure fractions were evaporated to dryness to afford(4-fluorodibenzo[b,d]furan-1-yl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol(320 mg, 83%) as a pale yellow oil. LC-MS (Method A): m/z (ES+),[M+H]+=413; base, HPLC t_(R)=1.543 min.

Intermediate D, 4-Fluorodibenzo[b,d]furan-1-carbaldehyde

BuLi (1.132 mL, 2.83 mmol) was added dropwise to1-bromo-4-fluorodibenzo[b,d]furan (500 mg, 1.89 mmol) in THF (10 mL) at−78° C. over a period of 0.5 hour under nitrogen.DMF (551 mg, 7.54 mmol)was added. The resulting mixture was stirred at −78° C. for 1 hour. Thereaction mixture was quenched with water (10 mL), extracted with EtOAc(3×10 mL), the organic layer was dried over Na₂SO₄, filtered andevaporated. The crude product was purified by flash silicachromatography, elution gradient 0 to 2% petroleum ether in EtOAc. Purefractions were evaporated to dryness to afford4-fluorodibenzo[b,d]furan-1-carbaldehyde (360 mg, 89%) as a white solid.

Intermediate C, 1-Bromo-4-fluorodibenzo[b,d]furan

BuLi (0.482 mL, 1.20 mmol) was added dropwise to1,3-difluoro-2-(2-iodophenoxy)benzene (100 mg, 0.30 mmol) in THF (10 mL)at −78° C. over a period of 0.5 hour under nitrogen. The resultingmixture was allowed to warm to 0° C. and stirred for 30 min. Aftercooling to −78° C., ethylene dibromide (85 mg, 0.45 mmol) was addeddropwise, and stirring continued at low temperature for further 30menthe warm to rt. The reaction mixture was quenched with water (10 mL),extracted with EtOAc (3×10 mL), the organic layer was dried over Na₂SO₄,filtered and evaporated. The residue was purified by preparative TLC(petroleum ether), to afford 1-bromo-4-fluorodibenzo[b,d]furan (55.0 mg,68.9%) as a white solid. ¹H NMR (300 MHz, DMSO-d6) δ ppm 7.43-7.72 (m,4H), 7.83-7.90 (m, 1H), 8.47 (d, 1H).

Intermediate B, 1,3-difluoro-2-(3-iodophenoxy)benzene

Sodium nitrite (206 mg, 2.94 mmol) in water (5 mL) was added dropwise to2-(2,6-difluorophenoxy)aniline (500 mg, 2.26 mmol) in HCl (6781 μL, 6.78mmol) at 0° C. The resulting mixture was stirred at 0° C. for 1 hour.Sodium iodide (847 mg, 5.65 mmol) in water (5 mL) was added dropwise.After 0.5 h the mixture was warmed to 100° C. for 1 h. Cooled to rt andextracted with EtOAc (10 mL×3).The combined organic layer was washedwith Na₂S₂O₃.5H₂O (30 mL) and dried with Na₂SO₄. The crude product waspurified by flash silica chromatography, elution gradient 0 to 2%petroleum ether in EtOAc. Pure fractions were evaporated to dryness toafford 1,3-difluoro-2-(2-iodophenoxy)benzene (530 mg, 70.6%) as a whitesolid. ¹H NMR (400 MHz, DMSO-d6) δ ppm 6.68 (dq, 1H), 6.92 (td, 1H),7.28-7.47 (m, 4H), 7.91 (dd, 1H).

Intermediate A, 3-(2,6-Difluorophenoxy)aniline

1-Fluoro-2-nitrobenzene (6.51 g, 46.12 mmol) was added to2,6-difluorophenol (5 g, 38.43 mmol) and K₂CO₃ (15.94 g, 115.30 mmol) inDMF (50 mL) at 25° C. under nitrogen. The resulting mixture was stirredat 100° C. for 12 hours. The reaction mixture was quenched with water(50 mL), extracted with EtOAc (3×50 mL), the organic layer was washedwith water (100 mL×3) and dried over Na₂SO₄, filtered and evaporated.The crude product was purified by flash silica chromatography, elutiongradient 0 to 10% petroleum ether in EtOAc. Pure fractions wereevaporated to dryness to afford 1,3-difluoro-2-(2-nitrophenoxy)benzene(9.50 g, 98%) as a yellow solid. Pd/C (4.02 g, 3.78 mmol) was added to1,3-difluoro-2-(2-nitrophenoxy)benzene (9.5 g, 37.82 mmol) in ethanol(100 mL) at 25° C. under hydrogen. The resulting mixture was stirred atrt for 2 hours. The mixture was filtered through a Celite pad. Thesolvent was removed under reduced pressure.2-(2,6-difluorophenoxy)aniline (7.50 g, 90%) as a brown oil was used inthe next step directly without further purification. ¹H NMR (300 MHz,DMSO-d6) δ ppm 5.09 (s, 2H), 6.32-6.48 (m, 2H), 6.70-6.85 (m, 2H),7.18-7.40 (m, 3H).

Example 54. (4-Fluoro-1-methyl-1H-indol-7-yl)(1H-imidazol-2-yl)methanol

TBAF (0.799 mL, 0.80 mmol) was added slowly to(4-fluoro-1-methyl-1H-indol-7-yl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol(200 mg, 0.53 mmol) in THF (7 mL) under nitrogen. The resulting solutionwas stirred at 50° C. for 6 hours. The solvent was removed under reducedpressure. The crude product was purified by flash C18-flashchromatography, elution gradient 0 to 70% MeCN in water. Pure fractionswere evaporated to dryness to afford(4-fluoro-1-methyl-1H-indol-7-yl)(1H-imidazol-2-yl)methanol (36.9 mg,28.2%) as a white solid. ¹H NMR (300 MHz, DMSO) δ ppm 4.00 (s, 3H),6.28-6.29 (m, 1H), 6.41-6.43 (m, 1H), 6.46-6.47 (m, 1H), 6.71-6.75 (m,1H), 6.92-7.00 (m, 2H), 7.02-7.04 (m, 1H), 7.27 (s, 1H), 11.96 (s, 1H).LC-MS (Method A): m/z (ES+), [M+H]+=246; acid, HPLC t_(R)=0.544 min.

Intermediate C,(4-Fluoro-1-methyl-1H-indol-7-yl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol

n-Butyllithium (1.255 mL, 3.14 mmol) was added slowly to1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (467 mg, 2.35 mmol) inTHF (8 mL) at −78° C. under nitrogen. 1 hours later, added1-ethyl-4-fluoro-1H-indole-7-carbaldehyde (300 mg, 1.57 mmol). Theresulting solution was stirred at −78° C. for 3 hours. The reactionmixture was quenched with saturated NH₄Cl (5 mL), extracted with EtOAc(2×10 mL), the organic layer was dried over Na₂SO₄, filtered andevaporated to afford white solid. The crude product was purified byflash silica chromatography, elution gradient 0 to 100% EtOAc inpetroleum ether. Pure fractions were evaporated to dryness to afford(1-ethyl-4-fluoro-1H-indol-7-yl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol(525 mg, 86%) as a white solid. ¹H NMR (300 MHz, DMSO) δ ppm −0.04-0.00(m, 12H), 0.81-0.85 (m, 2H), 1.16-1.18 (m, 1H), 1.20-1.26 (m, 2H), 1.99(s, 1H), 3.35-3.47 (m, 3H), 4.19 (s, 1H), 4.32 (s, 1H), 5.25-5.28 (m,1H), 5.58-5.60 (m, 1H), 6.25-6.27 (m, 1H), 6.40-6.41 (m, 1H), 5.52-5.53(m, 1H), 6.71-6.76 (m, 1H), 6.80 (s, 1H), 7.02-7.05 (m, 1H), 7.31-7.34(m, 2H). LC-MS (Method A): m/z (ES+), [M+H]+=390.1; acid, HPLCt_(R)=0.58 min.

Intermediate B, 4-Fluoro-1-methyl-1H-indole-7-carbaldehyde

Cs₂CO₃ (1997 mg, 6.13 mmol) was added to4-fluoro-1H-indole-7-carbaldehyde (500 mg, 3.06 mmol) in acetonitrile (8mL) warmed to 70° C. under nitrogen. 0.5 hour later, cooled to rt.,added iodomethane (870 mg, 6.13 mmol). The resulting mixture was stirredat 70° C. for 2 hour. The reaction mixture was filtered, the solvent wasremoved under reduced pressure. The crude product was purified by flashsilica chromatography, elution gradient 0 to 10% EtOAc in petroleumether. Pure fractions were evaporated to dryness to afford4-fluoro-1-methyl-1H-indole-7-carbaldehyde (337 mg, 62.1%) as a whiteliquid. ¹H NMR (300 MHz, DMSO) δ ppm 4.08-4.11 (m, 3H), 6.66-6.67 (m,1H), 7.01-7.07 (m, 1H), 7.49 (s, 1H), 7.80-7.83 (m, 1H), 10.32 (s, 1H).LC-MS (Method A): m/z (ES+), [M+H]+=177.95; acid, HPLC t_(R)=1.407 min.

Intermediate A, 4-Fluoro-1H-indole-7-carbaldehyde

n-Butyllithium (14.39 mL, 35.98 mmol) was added slowly to7-bromo-4-fluoro-1H-indole (2.2 g, 10.28 mmol) in THF (30 mL) at −78° C.under nitrogen, stirred for 15 minutes. Then slowly warmed to 5° C.,stirred for 30 minutes. Cooled to −78° C., added DMF (3.98 mL, 51.39mmol), slowly warmed to 25° C., stirred for 2 hours. The reactionmixture was quenched with water (50 mL), extracted with Et₂O (3×50 mL),the organic layer was dried over Na₂SO₄, filtered and evaporated toafford white solid. The crude product was purified by flash silicachromatography, elution gradient 0 to 10% EtOAc in petroleum ether. Purefractions were evaporated to dryness to afford4-fluoro-1H-indole-7-carbaldehyde (1.370 g, 82%) as a white solid. ¹HNMR (300 MHz, DMSO) δ ppm 6.64-6.66 (m, 1H), 7.02-7.08 (m, 1H),7.44-7.46 (m, 1H), 7.79-7.84 (m, 1H), 10.13 (s, 1H), 11.90 (s, 1H).LC-MS (Method A): m/z (ES+), [M+H]+=164; acid, HPLC t_(R)=1.052 min.

Example 55. Pure Enantiomer, Isomer 1,(4-Fluoro-1-methyl-1H-indol-7-yl)(1H-imidazol-2-yl)methanol

Example 54, (4-fluoro-1-methyl-1H-indol-7-yl)(1H-imidazol-2-yl)methanol(0.22 g, 0.90 mmol), was purified by preparative chiral-HPLC on aChiralpak IA column, eluting isocratically with 10% heptane in IPA(modified with Et₃N) as eluent. The fractions containing the desiredcompound were evaporated to dryness to afford(4-fluoro-1-methyl-1H-indol-7-yl)(1H-imidazol-2-yl)methanol (0.090 g,40.9%, Peak 1, Example 55) as a white solid and(4-fluoro-1-methyl-1H-indol-7-yl)(1H-imidazol-2-yl)methanol (0.110 g,50.0%, Peak 2, Example 56) as a white solid. ¹H NMR (300 MHz, CDCl₃) δppm 3.75 (s, 3H), 6.44 (s, 1H), 6.56 (d, 1H), 6.67 (dt, 1H), 6.88-6.96(m, 3H), 6.96-7.07 (m, 1H). LC-MS (Method A): m/z (ES+), [M+H]+=246;acid, HPLC t_(R)=1.26 min. Chiral analytical HPLC. CHIRALPAK AS-3,0.46×5 cm, 5 μM, Mobile Phase A hexanes (0.2% DEA), Mobile Phase Bisopropyl alcohol (90:10). Flow rate 1.0 mL/min, UV-vis detection 254nm. t_(R)=2.72 min.

Example 56. Pure Enantiomer, Isomer 2,(4-Fluoro-1-methyl-1H-indol-7-yl)(1H-imidazol-2-yl)methanol

Example 54, (4-fluoro-1-methyl-1H-indol-7-yl)(1H-imidazol-2-yl)methanol(0.22 g, 0.90 mmol), was purified by preparative chiral-HPLC on aChiralpak IA column, eluting isocratically with 10% heptane in IPA(modified with Et₃N) as eluent. The fractions containing the desiredcompound were evaporated to dryness to afford(4-fluoro-1-methyl-1H-indol-7-yl)(1H-imidazol-2-yl)methanol (0.090 g,40.9%, Peak 1, Example 55) as a white solid and(4-fluoro-1-methyl-1H-indol-7-yl)(1H-imidazol-2-yl)methanol (0.110 g,50.0%, Peak 2, Example 56) as a white solid. ¹H NMR (300 MHz, CDCl₃) δppm 3.73 (s, 3H), 6.45 (s, 1H), 6.56 (d, 1H), 6.68 (dt, 1H), 6.86-6.96(m, 3H), 6.96-7.08 (m, 1H). LC-MS (Method A): m/z (ES+), [M+H]+=246;acid, HPLC t_(R)=1.26 min. Chiral analytical HPLC. CHIRALPAK AS-3,0.46×5 cm, 5 μm, Mobile Phase A hexanes (0.2% DEA), Mobile Phase Bisopropyl alcohol (90:10). Flow rate 1.0 mL/min, UV-vis detection 254nm. t_(R)=4.82 min.

Example 57. (1-Ethyl-4-fluoro-1H-indol-7-yl)(1H-imidazol-2-yl)methanol

Example 55 was prepared in analogous fashion to Example 54. ¹H NMR (300MHz, DMSO) δ ppm 1.22-1.29 (m, 3H), 4.37-4.46 (m, 1H), 4.55-4.67 (m,1H), 6.27 (s, 2H), 6.50-6.51 (m, 1H), 6.71-6.78 (m, 2H), 7.01-7.08 (m,2H), 7.35-7.36 (m, 1H), 11.93 (s, 1H). LC-MS (Method A): m/z (ES+),[M+H]+=259.9; acid, HPLC t_(R)=1.375 min.

Example 58.(2,3-Dihydro-1H-pyrrolo[1,2-a]indol-5-yl)(1H-imidazol-2-yl)methanol

(2,3-Dihydro-1H-pyrrolo[1,2-a]indol-5-yl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol(120 mg, 0.31 mmol) was added to HCl/EtOAc (5 ml, 64.90 mmol) undernitrogen. The resulting solution was stirred at rt for 8 hours. Themixture was evaporated to afford the crude product as a purple solid.The crude product was purified by flash C18-flash chromatography,elution gradient 0 to 100% MeCN in water. Pure fractions were evaporatedto dryness to afford(2,3-dihydro-1H-pyrrolo[1,2-a]indol-5-yl)(1H-imidazol-2-yl)methanol(35.0 mg, 38.6%) as a purple solid. ¹H NMR (300 MHz, DMSO) δ ppm:2.54-2.59 (2H, m), 2.94-2.99 (2H, m) 3.96-4.04 (1H, m), 4.32-4.40 (1H,m), 6.25 (1H, s), 6.60 (1H, s), 6.23 (1H, s), 6.94-6.99 (1H, m),7.51-7.54 (1H, m), 7.62 (2H, s). LC-MS (Method A): m/z (ES+),[M+H]+=254.4; acid, HPLC t_(R)=1.30 min.

Intermediate H,(2,3-Dihydro-1H-pyrrolo[1,2-a]indol-5-yl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol

BuLi (112 mg, 1.75 mmol) was added to1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (209 mg, 1.05 mmol) inTHF (10 mL) dropwise at −78° C. under nitrogen. The resulting solutionwas stirred at −78° C. for 1 hour.2,3-dihydro-1H-pyrrolo[1,2-a]indole-5-carbaldehyde (130 mg, 0.70 mmol)was added dropwise. The resulting solution was stirred at −78° C. for 2hours. The reaction mixture was quenched with saturated NH₄Cl (10 mL),extracted with EtOAc (2×15 mL), the organic layer was dried over Na₂SO₄,filtered and evaporated to afford colorless residue. The crude productwas purified by flash C18-flash chromatography, elution gradient 0 to100% MeCN in water. Pure fractions were evaporated to dryness to afford(2,3-dihydro-1H-pyrrolo[1,2-a]indol-5-yl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol(150 mg, 55.7%) as a colorless gum. LC-MS (Method A): m/z (ES+),[M+H]+=384; acid, HPLC t_(R)=0.84 min.

Intermediate G, 2,3-Dihydro-1H-pyrrolo[1,2-a]indole-5-carbaldehyde

Manganese dioxide (65.0 mg, 0.75 mmol) was added to(2,3-dihydro-1H-pyrrolo[1,2-a]indol-5-yl)methanol (140 mg, 0.75 mmol) inDCM (10 mL) under nitrogen. The resulting solution was stirred at rt for16 hours. The solid was filtered out. The filtrate was evaporated toafford 2,3-dihydro-1H-pyrrolo[1,2-a]indole-5-carbaldehyde (130 mg, 94%)as a white solid. LC-MS (Method A): m/z (ES+), [M+H]+=186.0; acid, HPLCt_(R)=0.97 min.

Intermediate F, (2,3-Dihydro-1H-pyrrolo[1,2-a]indol-5-yl)methanol

LiAlH₄ (11.32 mg, 0.30 mmol) was added to2,3-dihydro-1H-pyrrolo[1,2-a]indole-5-carboxylic acid (60 mg, 0.30 mmol)in THF (5 mL) cooled to 0° C. under nitrogen. The resulting solution wasstirred at rt for 2 hours. The reaction mixture was quenched withsaturated NH₄Cl (10 mL), extracted with EtOAc (2×10 mL), the organiclayer was dried over Na2SO4, filtered and evaporated to afford(2,3-dihydro-1H-pyrrolo[1,2-a]indol-5-yl)methanol (42.0 mg, 75%) as awhite solid. LC-MS (Method A): m/z (ES+), [M+H]+=188.2; acid, HPLCt_(R)=0.81 min.

Intermediate E, 2,3-Dihydro-1H-pyrrolo[1,2-a]indole-5-carboxylic acid

Potassium 2-methylpropan-2-olate (46.3 mg, 0.41 mmol) was added tomethyl 2-(3-(tosyloxy)propyl)-1H-indole-7-carboxylate (160 mg, 0.41mmol) in BuOH (5 mL) at 25° C. under nitrogen. The resulting solutionwas stirred at 100° C. for 30 minutes. The reaction mixture wasacidified with 2M HCl. The reaction mixture was diluted with EtOAc (20mL), and washed sequentially with saturated brine (10 mL). The organiclayer was dried over Na₂SO₄, filtered and evaporated to afford2,3-dihydro-1H-pyrrolo[1,2-a]indole-5-carboxylic acid (62.0 mg, 74.6%)as a white solid. LC-MS (Method A): m/z (ES+), [M+H]+=202.2; acid, HPLCt_(R)=0.86 min.

Intermediate D, Methyl 2-(3-(tosyloxy)propyl)-1H-indole-7-carboxylate

4-Methylbenzene-1-sulfonyl chloride (147 mg, 0.77 mmol) was added tomethyl 2-(3-hydroxypropyl)-1H-indole-7-carboxylate (180 mg, 0.77 mmol)and Et3N (0.108 mL, 0.77 mmol) in DCM (10 mL) at 25° C. under nitrogen.The resulting solution was stirred at rt for 4 hours. The crude productwas purified by flash silica chromatography, elution gradient 0 to 50%EtOAc in petroleum ether. Pure fractions were evaporated to dryness toafford methyl 2-(3-(tosyloxy)propyl)-1H-indole-7-carboxylate (260 mg,87%) as a white solid. LC-MS (Method A): m/z (ES+), [M+H]+=388.0; acid,HPLC t_(R)=1.09 min.

Intermediate C, Methyl 2-(3-hydroxypropyl)-1H-indole-7-carboxylate

Pd/C (157 mg, 0.15 mmol) and methyl5-bromo-2-(3-hydroxypropyl)-1H-indole-7-carboxylate (230 mg, 0.74 mmol)in MeOH (10 mL) was stirred under an atmosphere of nitrogen at 1 atm andrt for 4 hours. The solvent was removed. The crude product was purifiedby flash C18-flash chromatography, elution gradient 0 to 80% MeCN inwater. Pure fractions were evaporated to dryness to afford methyl2-(3-hydroxypropyl)-1H-indole-7-carboxylate (100 mg, 58.2%) as acolorless gum. ¹H NMR (300 MHz, DMSO) δ ppm: 1.17 (2H, m), 2.85 (2H, m),3.48 (2H, m), 3.92 (3H, s), 4.59 (1H, m), 6.28 (1H, m), 7.05 (1H, m),7.66-7.73 (2H, m), 10.85 (1H, s). LC-MS (Method A): m/z (ES+),[M+H]+=234.2; acid, HPLC t_(R)=0.83 min.

Intermediate B, Methyl5-bromo-2-(3-hydroxypropyl)-1H-indole-7-carboxylate

NaAuCl₄.2H₂O (49.3 mg, 0.13 mmol) was added to methyl2-amino-5-bromo-3-(5-hydroxypent-1-yn-1-yl)benzoate (400 mg, 1.28 mmol)in ethanol (2 mL) at 25° C. The resulting solution was stirred at 25° C.for 16 hours. The crude product was purified by flash silicachromatography, elution gradient 0 to 80% EtOAc in petroleum ether. Purefractions were evaporated to dryness to afford methyl5-bromo-2-(3-hydroxypropyl)-1H-indole-7-carboxylate (230 mg, 57.5%) asan orange solid. LC-MS (Method A): m/z (ES+), [M+H]+=312.0; acid, HPLCt_(R)=1.11 min

Intermediate A, methyl 2-amino-5-bromo-3-(5-hydroxypent-1-ynyl)benzoate

Pent-4-yn-1-ol (35.4 mg, 0.42 mmol), methyl2-amino-5-bromo-3-iodobenzoate (100 mg, 0.28 mmol),PdCl₂(PPh₃)₂ (45.9mg, 0.06 mmol), DIEA (0.098 mL, 0.56 mmol) and copper(I) iodide (10.70mg, 0.06 mmol) were suspended in THF (2 mL) under nitrogen. The reactionwas stirred at rt for 2 hours. The solvent was removed. The crudeproduct was purified by flash silica chromatography, elution gradient 0to 80% EtOAc in petroleum ether. Pure fractions were evaporated todryness to afford methyl2-amino-5-bromo-3-(5-hydroxypent-1-yn-1-yl)benzoate (80 mg, 91%) as abrown solid (80 mg, 91%). ¹H NMR (300 MHz, CDCl₃-d6) δ ppm 1.67-1.76(2H, m), 2.50-2.57 (2H, m), 3.50-3.82 (2H, m), 3.82 (3H, s), 4.58 (1H,tr), 6.76 (2H, brs), 7.52 (1H, d), 7.79 (1H, d). LC-MS (Method A): m/z(ES+), [M+H]+=312.2; acid, HPLC t_(R)=1.54 min.

Example 59, (4-Fluoro-8-methylnaphthalen-1-yl)(1H-imidazol-2-yl)methanol

HCl/EtOAc (15 mL) was added to(4-fluoro-8-methylnaphthalen-1-yl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol(250 mg, 0.65 mmol) at rt. The resulting mixture was stirred at rt for12 hours. The solvent was removed under reduced pressure. The crudeproduct was purified by preparative HPLC (XSelect CSH Prep C18 OBDcolumn, 5μ silica, 19 mm diameter, 150 mm length), using decreasinglypolar mixtures of water (containing 0.1% Formic acid) and MeCN aseluents. Fractions containing the desired compound were evaporated todryness to afford(4-fluoro-8-methylnaphthalen-1-yl)(1H-imidazol-2-yl)methanol (70.0 mg,35.7%) as a white solid. ¹H NMR (400 MHz, Methanol-d4) δ ppm 3.01 (3H,s), 7.08 (1H, s), 7.12-7.25 (3H, m), 7.34 (1H, t), 7.45-7.54 (2H, m),8.07 (1H, dt), 8.33 (1H, s). LC-MS (Method A): m/z (ES+), [M+H]+=257;base, HPLC t_(R)=1.411 min.

Intermediate J,(4-Fluoro-8-methylnaphthalen-1-yl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol

BuLi (0.638 mL, 1.59 mmol) was added dropwise to1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (316 mg, 1.59 mmol) inTHF (10 mL) at −78° C. over a period of 0.5 hour under nitrogen.4-fluoro-8-methyl-1-naphthaldehyde (150 mg, 0.80 mmol) was added at −78°C. The resulting mixture was stirred at −78° C. for 1 hour. The reactionmixture was quenched with water (10 mL), extracted with EtOAc (3×10 mL),the organic layer was dried over Na₂SO₄, filtered and evaporated. Thecrude product was purified by flash C18-flash chromatography, elutiongradient 0 to 100% water in MeCN. Pure fractions were evaporated todryness to afford(4-fluoro-8-methylnaphthalen-1-yl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol(270 mg, 88%) as a brown solid. LC-MS (Method A): m/z (ES+), [M+H]+=387;acid, HPLC t_(R)=0.888 min.

Intermediate I, 4-Fluoro-8-methyl-1-naphthaldehyde

PdCl₂(dppf)-CH₂Cl₂adduct (25.3 mg, 0.03 mmol) was added to5-fluoro-8-formylnaphthalen-1-yl trifluoromethanesulfonate (50 mg, 0.16mmol), trimethylboroxine (97 mg, 0.78 mmol) and K₂CO₃ (64.3 mg, 0.47mmol) in DME (2 mL) and water (1 mL) under nitrogen. The resultingmixture was stirred at 85° C. for 2 hours. The reaction mixture wasdiluted with EtOAc (10 mL), and washed with water (5 mL×3).The organiclayer was dried over Na₂SO₄, filtered and evaporated. The residue waspurified by preparative TLC (EtOAc:petroleum ether=1:10), to afford4-fluoro-8-methyl-1-naphthaldehyde (20.00 mg, 68.5%) as a pale yellowsolid.

Intermediate H, 5-Fluoro-8-formylnaphthalen-1-yltrifluoromethanesulfonate

Tf₂O (1.237 mL, 7.32 mmol) was added to4-fluoro-8-hydroxy-1-naphthaldehyde (1.16 g, 6.10 mmol) and pyridine(0.740 mL, 9.15 mmol) in DCM (20 mL) at 0° C. under nitrogen. Theresulting mixture was stirred at rt for 2 hours. The reaction mixturewas quenched with water (10 mL), extracted with DCM (3×10 mL), theorganic layer was dried over Na2SO4, filtered and evaporated. The crudeproduct was purified by flash silica chromatography, elution gradient 0to 2% EtOAc in petroleum ether. Pure fractions were evaporated todryness to afford 5-fluoro-8-formylnaphthalen-1-yltrifluoromethanesulfonate (1.100 g, 56.0%) as a orange solid. ¹HNMR (300MHz, DMSO-d6) δ ppm 7.73 (1H, m), 7.92 (1H, m), 7.99-8.09 (1H, m), 8.24(1H, m), 8.37 (1H, m), 10.69 (1H, s).

Intermediate G 4-Fluoro-8-hydroxy-1-naphthaldehyde

Boron trichloride (2.283 mL, 2.28 mmol) was added dropwise to8-(benzyloxy)-4-fluoro-1-naphthaldehyde (320 mg, 1.14 mmol) in DCM (10mL) at 0° C. under nitrogen. The resulting mixture was stirred at 0° C.for 50 minutes. The reaction mixture was quenched with 2M HCl (5 mL),extracted with DCM (3×5 mL), the organic layer was dried over Na₂SO₄,filtered and evaporated. The crude product was purified by flash silicachromatography, elution gradient 0 to 2% petroleum ether in EtOAc. Purefractions were evaporated to dryness to afford4-fluoro-8-hydroxy-1-naphthaldehyde (200 mg, 92%) as a orange solid.

Intermediate F, 8-(Benzyloxy)-4-fluoro-1-naphthaldehyde

BuLi (49.3 mg, 0.77 mmol) was added dropwise to5-(benzyloxy)-4-bromo-1-fluoronaphthalene (170 mg, 0.51 mmol) in THF (10mL) at −78° C. over a period of 0.5 hour under nitrogen.DMF (0.159 mL,2.05 mmol) was added. The resulting solution was stirred at −78° C. for1 hour. The reaction mixture was quenched with water (10 mL), extractedwith EtOAc (3×5 mL), the organic layer was dried over Na₂SO₄, filteredand evaporated to afford 8-(benzyloxy)-4-fluoro-1-naphthaldehyde (130mg, 90%) as a yellow solid. The product was used in the next stepdirectly without further purification.

Intermediate E, 5-(Benzyloxy)-4-bromo-1-fluoronaphthalene

alpha-Bromotoluene (180 mg, 1.05 mmol) was added dropwise to8-bromo-5-fluoronaphthalen-1-ol (230 mg, 0.95 mmol) and Cs₂CO₃ (622 mg,1.91 mmol) in acetone (5 mL) at 25° C. under nitrogen. The resultingmixture was stirred at rt for 1 hour. The reaction mixture was quenchedwith water (10 mL), extracted with EtOAc (3×5 mL), the organic layer wasdried over Na₂SO₄, filtered and evaporated to afford pale yellow solid.The crude product was purified by flash silica chromatography, elutiongradient 0 to 10% petroleum ether in EtOAc. Pure fractions wereevaporated to dryness to afford5-(benzyloxy)-4-bromo-1-fluoronaphthalene (170 mg, 53.8%) as a paleyellow solid.

Intermediate D, 8-Bromo-5-fluoronaphthalen-1-ol

Trimethylphenylammonium tribromide (155 mg, 0.41 mmol) was added slowlyto 8-bromo-5-fluoro-3,4-dihydronaphthalen-1(2H)-one (100 mg, 0.41 mmol)in THF (5 mL) at 25° C. The resulting mixture was stirred at rt for 45minutes. The reaction mixture was quenched with water (5 mL), extractedwith EtOAc (3×5 mL), the organic layer was washed with water (20 mL) anddried over Na₂SO₄, filtered and evaporated to afford pale yellow oil.The residue was dissolved in DMF (5 mL) and lithium bromide (71.5 mg,0.82 mmol) and lithium carbonate (97 mg, 1.32 mmol) was added. Thesuspension was heated at 130° C. for 1 h, cooled to rt, and the solidwas removed by filtration (EtOAc (20 mL)),the filtrate was washed withwater (3×10 mL) and dried by Na₂SO₄. The solvent was removed underreduced pressure. The crude product was purified by flash silicachromatography, elution gradient 0 to 5% petroleum ether in EtOAc. Purefractions were evaporated to dryness to afford8-bromo-5-fluoronaphthalen-1-ol (63.0 mg, 63.5%) as a pale yellow solid.

Intermediate C, 8-Bromo-5-fluoro-3,4-dihydronaphthalen-1(2H)-one

PPA (20 mL, 10.72 mmol) was added to 4-(5-bromo-2-fluorophenyl)butanoicacid (2.8 g, 10.72 mmol).The resulting mixture was stirred at 120° C.for 2 hours. The reaction mixture was poured into ice water (100 mL),extracted with EtOAc (3×30 mL), the organic layer was dried over Na2SO4,filtered and evaporated to afford pale yellow solid. The residue waspurified by preparative TLC (EtOAc:petroleum ether=1:20), to afford8-bromo-5-fluoro-3,4-dihydronaphthalen-1(2H)-one (0.50 g, 19.1%) as aorange solid.

Intermediate B, 4-(5-Bromo-2-fluorophenyl)butanoic acid

Platinum(IV) oxide (1.08 mg, 4.79 μmol) was added to tert-butyl4-(5-bromo-2-fluorophenyl)but-3-ynoate (50 mg, 0.16 mmol), Ammoniumhydroxide (0.056 mg, 1.60 μmol) in MeOH (5 mL) at 25° C. under hydrogen.The resulting mixture was stirred at rt for 12 hours. The mixture wasfiltered through a Celite pad. The solvent was removed under reducedpressure. tert-Butyl 4-(5-bromo-2-fluorophenyl)butanoate (45.0 mg, 89%)as a pale yellow oil was used in the next step directly without furtherpurification. NaOH (10 mL, 10.00 mmol) was added to tert-butyl4-(5-bromo-2-fluorophenyl)butanoate (140 mg, 0.44 mmol) in MeOH (5 mL)at 25° C. The resulting mixture was stirred at 50° C. for 4 hours. Thereaction mixture was adjusted to pH=3-4 with 2M HCl. The reactionmixture was extracted with EtOAc (10 mL×2).The organic layer was driedover Na₂SO₄, filtered and evaporated to afford4-(5-bromo-2-fluorophenyl)butanoic acid (100 mg, 87%) as a yellow oil.

Intermediate A, tert-Butyl 4-(5-bromo-2-fluorophenyl)but-3-ynoate

Copper(I) iodide (7.18 mg, 0.04 mmol) was added to4-bromo-2-ethynyl-1-fluorobenzene (150 mg, 0.75 mmol) and tert-butyl2-diazoacetate (107 mg, 0.75 mmol) in acetonitrile (10 mL) at rt. Theresulting mixture was stirred at rt for 1 hour. The reaction mixture wasdiluted with EtOAc (25 mL), and washed sequentially with water (10mL×3), saturated brine (10 mL×2).The organic layer was dried overNa₂SO₄, filtered and evaporated to afford crude product. The crudeproduct was purified by flash silica chromatography, elution gradient100 to 1% petroleum ether in EtOAc. Pure fractions were evaporated todryness to afford tert-butyl 4-(5-bromo-2-fluorophenyl)but-3-ynoate (100mg, 42.4%) as a yellow oil.

Example 60. (1-Ethyl-5-fluoro-indolizin-8-yl)-(1H-imidazol-2-yl)methanol

n-BuLi (0.0960 mL, 0.241 mmol, 2.50 M solution in hexanes) was added toa mixture of 1-(diethoxymethyl)imidazole (41.0 mg, 0.241 mmol) in THF(0.500 mL) at −45° C. The mixture was stirred for 15 m and then cooledto −60° C. A solution of 1-ethyl-5-fluoro-indolizine-8-carbaldehyde(23.0 mg, 0.120 mmol) in THF (0.500 mL) was added. The mixture wasstirred for 10 m at −60° C. and then warmed to 0° C. over 1 h. Themixture was diluted with 0.100 M HCl and EtOAc, and the organic phasewas extracted with 0.100 M HCl (4×10.0 mL). The combined aqueous phaseswere cautiously diluted with sat. NaHCO₃, and the aqueous mixture wasextracted with EtOAc (4×10.0 mL). The combined organic phases were dried(MgSO₄) and concentrated under reduced pressure. The product waspurified by silica gel chromatography, eluting with DCM and MeOH (0-10%)to provide the title compound as a solid (12.2 mg, 38%). ¹H NMR (500MHz, MeOD) δ ppm 1.17 (t, J=7.5 Hz, 3H), 2.81 (ddd, J=15.0, 7.5, 3.0 Hz,2H), 6.15 (dd, J=7.4, 6.1 Hz, 1H), 6.33 (s, 1H), 6.62 (t, J=6.8 Hz, 1H),6.73 (d, J=2.9 Hz, 1H), 7.00 (s, 2H), 7.37 (d, J=2.8 Hz, 1H); LC-MS(Method C): m/z (ES+), [M+H]+=260.27; HPLC t_(R)=2.10 m.

Intermediate H, 1-Ethyl-5-fluoro-indolizine-8-carbaldehyde

n-BuLi (0.061 mL, 0.152 mmol, 2.50 M solution in hexanes) was added to acooled solution of 8-bromo-1-ethyl-5-fluoro-indolizine (35.0 mg, 0.145mmol) in THF (1.40 mL) at −78° C. The resulting solution was stirred for20 min at −78° C., and methyl formate (0.0180 mL, 0.289 mmol) was added.The mixture was stirred for 10 m at −78° C. and then warmed to 23° C.The mixture was diluted with water, and the aqueous phase was extractedwith EtOAc (3×10.0 mL). The combined organic phases were dried (MgSO₄),filtered, and concentrated under reduced pressure. The product waspurified by silica gel chromatography, eluting with hexanes and EtOAc(0-60%) to provide the title compound as a solid (16.0 mg, 58%). ¹H NMR(500 MHz, CDCl₃) δ 1.29 (t, J=5.5 Hz, 3H), 3.09 (q, J=7.5 Hz, 2H), 6.23(dd, J=7.5, 5.4 Hz, 1H), 6.86 (d, J=2.8 Hz, 1H), 7.39 (dd, J=7.5, 6.2Hz, 1H), 7.42 (d, J=2.9 Hz, 1H), 10.14 (s, 1H); LC-MS (Method C): m/z(ES+), [M+H]+ 192.21; (A05), HPLC t_(R)=2.69 min.

Intermediate G, 8-Bromo-1-ethyl-5-fluoro-indolizine

CuBr (7.90 mg, 0.0560 mmol) and Et₃N (0.0260 mL, 0.186 mmol) were addedto a mixture of 3-bromo-2-(1-ethylpropa-1,2-dienyl)-6-fluoro-pyridine(45.0 mg, 0.186 mmol) in DMA (2.10 mL). The mixture was stirred for 5 hat 130° C. with protection from light. The mixture was cooled to 23° C.and diluted with sat. NH₄Cl. The aqueous phase was extracted with EtOAc(3×10 mL), and the combined organic phases were washed with brine, dried(MgSO₄), filtered, and concentrated under reduced pressure. The productwas purified by silica gel chromatography, eluting with hexanes andEtOAc (0-40%) to provide the title compound as an oil (36.0 mg, 80%). ¹HNMR (500 MHz, CDCl₃) δ 1.29 (t, J=7.5 Hz, 3H), 3.13 (q, J=7.5 Hz, 2H),5.94 (dd, J=7.6, 5.6 Hz, 1H), 6.75 (d, J=2.8 Hz, 1H), 6.78 (dd, J=7.6,5.5 Hz, 1H), 7.29 (d, J=2.8 Hz, 1H); m/z: no ionization.

Intermediate F, 3-Bromo-2-(1-ethylpropa-1,2-dienyl)-6-fluoro-pyridine

A suspension of CuCN (317 mg, 3.54 mmol) in dry THF (7.00 mL) was cooledto −50° C. under nitrogen. To this was added EtLi (7.08 mL, 3.54 mmol,0.500 M in benzene), and the suspension was stirred for 30 m at −50° C.A cooled solution of 3-(3-bromo-6-fluoro-2-pyridyl)prop-2-ynylmethanesulfonate (436 mg, 1.42 mmol) in dry THF (7.00 mL) at −50° C. wastransferred with a cannula. The mixture was stirred for 2 h at −78° C.and warmed to 23° C. The mixture was diluted with a 10:1 mixture ofNH₄Cl and NH₄OH. (15.0 mL). The aqueous phase was extracted with EtOAc(3×15.0 mL), and the combined organic phases were dried (MgSO₄),filtered, and concentrated under reduced pressure. The product waspurified by silica gel chromatography, eluting with hexanes and EtOAc(0-40%) to provide the title compound as an oil (217 mg, 63%). ¹H NMR(500 MHz, CDCl3) δ 1.01 (t, J=7.4 Hz, 3H), 2.40 (ddq, J=10.9, 7.3, 3.5Hz, 2H), 4.99 (t, J=3.5 Hz, 2H), 6.62 (dd, J=8.5, 3.8 Hz, 1H), 7.84 (dd,J=8.5, 7.3 Hz, 1H); LC-MS (Method C): m/z (ES+), [M+H]+=242.12, 244.17;HPLC t_(R)=2.83 m.

Intermediate E, 3-(3-Bromo-6-fluoro-2-pyridyl)prop-2-ynylmethanesulfonate

DIPEA (0.315 mL, 1.81 mmol) and methanesulfonyl chloride (0.140 mL, 1.81mmol) were added to a mixture of3-(3-bromo-6-fluoro-2-pyridyl)prop-2-yn-1-ol (104 mg, 0.452 mmol) in DCM(1.90 mL) at 0° C. under nitrogen. The mixture was stirred at 23° C. for1 h, and then diluted with aqueous 1N HCl. The aqueous phase wasextracted with EtOAc (3×10.0 mL), and the combined organic phases werewashed with brine, dried (MgSO₄), filtered, and concentrated underreduced pressure. The product was purified by silica gel chromatography,eluting with hexanes and EtOAc (0-60%) to provide the title compound asan oil (108 mg, 77%). ¹H NMR (500 MHz, CDCl₃) δ 3.24 (s, 3H), 5.17 (s,2H), 6.91 (dd, J=8.7, 3.4 Hz, 1H), 8.00 (dd, J=8.7, 6.9 Hz, 1H); LC-MS(Method C): m/z (ES+), [M+H]+=308.09, 310.10; HPLC t_(R)=2.17 m.

Intermediate D, 3-(3-Bromo-6-fluoro-2-pyridyl)prop-2-yn-1-ol

NaNO₂ (63.1 mg, 0.914 mmol) was added to a solution of(dimethyl)silyl]oxyprop-1-ynyl]pyridin-2-amine (208 mg, 0.609 mmol) inHF.Pyridine (0.900 mL) at −10° C. The mixture was stirred for 1 h at−10° C. and then diluted with water. The aqueous phase was extractedwith DCM (3×10 mL), and the combined organic phases were washed withbrine, dried (MgSO₄), filtered, and concentrated under reduced pressure.The product was purified by silica gel chromatography, eluting withhexanes and EtOAc (0-60%) to provide the title compound as a solid(104.0 mg, 74%). ¹H NMR (500 MHz, CDCl₃) δ 2.07 (t, J=6.4 Hz, 1H), 4.59(d, J=6.3 Hz, 2H), 6.85 (dd, J=8.6, 3.4 Hz, 1H), 7.97 (dd, J=8.6, 7.0Hz, 1H); LC-MS (Method C): m/z (ES+), [M+H]+=230.15, 232.15; HPLCt_(R)=1.59 min.

Intermediate C,5-Bromo-6-[3-[tert-butyl(dimethyl)silyl]oxyprop-1-ynyl]pyridin-2-amine

NBS (20.7 mg, 0.117 mmol) was added to a solution of6-[3-[tert-butyl(dimethyl)silyl]oxyprop-1-ynyl]pyridin-2-amine (30.0 mg,0.114 mmol) in MeOH (0.350 mL) at 0° C. The mixture was stirred for 20 mat 23° C. and then diluted with water. The aqueous phase was extractedwith DCM (3×10 mL), and the combined organic phases were washed withbrine (50.0 mL), dried (MgSO₄), filtered, and concentrated under reducedpressure to provide the title compound as a solid (208 mg, 100%). Theproduct was used in the next step without further purification. ¹H NMR(500 MHz, CDCl3) δ 0.19 (s, 6H), 0.94 (s, 9H), 4.60 (s, 4H), 6.36 (d,J=8.7 Hz, 1H), 7.55 (d, J=8.7 Hz, 1H); LC-MS (Method C): m/z (ES+),[M+H]+=341.20, 343.21; HPLC t_(R)=3.00 m.

Intermediate B,6-[3-[tert-Butyl(dimethyl)silyl]oxyprop-1-ynyl]pyridin-2-amine

Et₃N (0.223 mL, 1.604 mmol), tert-butyldimethylsilyl chloride (174.6 mg,1.158 mmol) and 4-dimethylaminopyridine (10.9 mg, 0.0890 mmol) wereadded to a mixture of 3-(6-amino-2-pyridyl)prop-2-yn-1-ol (132 mg, 0.891mmol) in DCM (7.20 mL) at 0° C. under nitrogen. The mixture was stirredat 23° C. for 6 h and then diluted with water. The aqueous phase wasextracted with DCM (3×10.0 mL), and the combined organic phases werewashed with brine, dried (MgSO₄), filtered, and concentrated underreduced pressure. The product was purified by silica gel chromatography,eluting with hexanes and EtOAc (0-100%) to provide the title compound asa solid (168.0 mg, 72%). ¹H NMR (500 MHz, CDCl3) δ 0.14 (s, 6H), 0.91(s, 9H), 4.52 (s, 2H), 4.55 (s, 2H), 6.43 (dd, J=8.3, 0.6 Hz, 1H), 6.80(dd, J=7.4, 0.6 Hz, 1H), 7.35 (dd, J=8.3, 7.4 Hz, 1H); m/z (ES+),[M+H]+=263.34; (B05), HPLC tR=2.84 min.

Intermediate A, 3-(6-Amino-2-pyridyl)prop-2-yn-1-ol

Propargyl alcohol (0.101 mL, 1.73 mmol) was added to a mixture ofPdCl₂(PPh₃)₂ (40.6 mg, 0.0580 mmol), PPh₃ (33.4 mg, 0.127 mmol), CuI(22.0 mg, 0.115 mmol), and 2-amino-6-bromopyridine (200.0 mg, 1.16 mmol)in THF (4.20 mL) and Et₃N (0.242 mL, 1.73 mmol). The mixture was stirredfor 2 days at 23° C. The mixture was diluted with saturated NH₄Cl, andthe aqueous phase was extracted with EtOAc (2×10.0 mL). The combinedorganic phases were dried (MgSO₄), filtered, and concentrated underreduced pressure. The product was purified by silica gel chromatography,eluting with DCM and MeOH (0-10%) to provide the title compound as asolid (112 mg, 65%). ¹H NMR (500 MHz, MeOD) δ 4.38 (s, 2H), 6.53 (d,J=8.4 Hz, 1H), 6.72 (d, J=7.2 Hz, 1H), 7.40 (dd, J=8.4, 7.3 Hz, 1H);LC-MS (Method C) m/z (ES+), [M+H]+=149.14; HPLC tR=0.56 min.

Example 61.(3-Chloro-8-fluoro-indolizin-5-yl)-(1H-imidazol-2-yl)methanol

1.00 1M TBAF in THF (0.260 mL, 0.260 mmol) was added to a mixture of(3-chloro-8-fluoro-indolizin-5-yl)-[1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]methanol(34.0 mg, 0.0900 mmol) in THF (2.50 mL) at 23° C. under nitrogen. Themixture was refluxed for 3 h, and diluted with sat. NaHCO₃ (10.0 mL).The aqueous phase was extracted with EtOAc (3×25.0 mL), and the combinedorganic phases were washed with brine (25.0 mL), dried (MgSO₄),filtered, and concentrated under reduced pressure. The product waspurified by silica gel chromatography (12 g cartridge) with hexane andEtOAc (0-100%) to provide the title compound as a solid (11.0 mg, 48%).¹H NMR (500 MHz, MeOD) δ 7.14 (s, 1H), 7.06 (s, 2H), 6.72 (d, J=4.3 Hz,1H), 6.69 (d, J=4.3 Hz, 1H), 6.42 (d, J=9.2 Hz, 2H). LC-MS (Method C):m/z (ES+), [M+H]⁺=266.0. HPLC t_(R)=2.23 m.

Intermediate F.(3-Chloro-8-fluoro-indolizin-5-yl)-[1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]methanol

2.50 M n-BuLi in THF (0.260 mL, 0.640 mmol) was added to a mixture of2-(imidazol-1-ylmethoxy)ethyl-trimethyl-silane (127 mg, 0.640 mmol) inTHF (4.00 mL) at −78° C. under nitrogen. The mixture was stirred at −78°C. for 1 h, and added dropwise to a cooled solution of3-chloro-8-fluoro-indolizine-5-carbaldehyde (97.0 mg, 0.490 mmol) in THF(2 mL) at −78° C. The mixture was stirred at −78° C. for 20 m, andwarmed to 0° C. for 20 m. The mixture was diluted with NH₄Cl (10.0 mL).The aqueous phase was extracted with EtOAc (3×25.0 mL), and the combinedorganic phases were washed with brine (50.0 mL), dried (MgSO₄),filtered, and concentrated under reduced pressure. The product waspurified by silica gel chromatography (24 g cartridge) with hexane andEtOAc (0-70%) to provide the title compound as a solid (36.0 mg, 19%).¹H NMR (500 MHz, CDCl₃) δ 7.19 (s, 1H), 7.05 (d, J=2.9 Hz, 2H),6.72-6.66 (m, 2H), 6.36-6.24 (m, 2H), 5.27 (q, J=10.8 Hz, 2H), 3.95 (s,1H), 3.56-3.35 (m, 2H), 0.79 (ddd, J=10.3, 6.4, 5.4 Hz, 3H), −0.04 (s,9H). LC-MS (Method C): m/z (ES+), [M+H]⁺=396.0. HPLC t_(R)=3.05 min.

Intermediate E. 3-Chloro-8-fluoro-indolizine-5-carbaldehyde

4 Å Molecular sieves were added to a mixture of NMO (144 mg, 1.23 mmol)and (3-chloro-8-fluoro-indolizin-5-yl)methanol (123 mg, 0.620 mmol) inDCM (5.00 mL) at 23° C. under nitrogen. The mixture was stirred for 20m. TPAP (10.8 mg, 0.0300 mmol) was added, and the mixture was stirredfor 10 m then filtered through a pad of Florisil. The filtrate wasconcentrated under reduced pressure, and the product was purified bysilica gel chromatography (24 g cartridge) with hexane and EtOAc (0-30%)to provide the title compound as a solid (97.0 mg; 80%). ¹H NMR (500MHz, CDCl₃) δ 10.86 (d, J=0.5 Hz, 1H), 7.47 (dd, J=8.0, 5.6 Hz, 1H),6.91 (d, J=4.4 Hz, 1H), 6.84 (d, J=4.4 Hz, 1H), 6.51 (dd, J=9.3, 8.0 Hz,1H). LC-MS (Method C): m/z (ES+), [M+H]⁺=198.1. HPLC t_(R)=2.67 min.

Intermediate D. (3-Chloro-8-fluoro-indolizin-5-yl)nethanol

1.00 M LAH in THF (0.620 mL, 0.620 mmol) was added to a mixture of ethyl3-chloro-8-fluoro-indolizine-5-carboxylate (150 mg, 0.620 mmol) in THF(10.0 mL) at 0° C. under nitrogen. The mixture was stirred at 23° C. for20 m then diluted with water (1.00 mL), 1M NaOH (2.00 mL) and water(1.00 mL). The mixture was filtered through Celite, and the solid waswashed with EtOAc (10.0 mL). The filtrate was concentrated under reducedpressure to provide the title compound as a solid (123 mg; 99%). ¹H NMR(500 MHz, CDCl₃) δ 6.72 (d, J=4.3 Hz, 1H), 6.68 (d, J=4.3 Hz, 1H), 6.52(dd, J=7.6, 5.4 Hz, 1H), 6.33 (dd, J=9.8, 7.6 Hz, 1H), 5.16 (s, 2H).LC-MS (Method C): m/z (ES+), [M+H]⁺=200.2. t_(R)=2.53 min.

Intermediate C. Ethyl 3-chloro-8-fluoro-indolizine-5-carboxylate

A solution of NCS (419 mg, 3.14 mmol) in DCM (10.0 mL) was addeddrop-wise to a mixture of ethyl 8-fluoroindolizine-5-carboxylate (591mg, 2.85 mmol) in DCM (20.0 mL) at 0° C. under nitrogen. The mixture wasstirred in the dark at 0° C. for 3.5 h and then diluted with 1M Na₂S₂O₃(50.0 mL). The aqueous phase was extracted with DCM (3×50.0 mL), and thecombined organic phases were washed with brine (50.0 mL), dried (MgSO₄),filtered, and concentrated under reduced pressure. The product waspurified by silica gel chromatography (40 g cartridge) with hexane(100%) to provide the title compound as solid (656 mg, 95%). ¹H NMR (500MHz, CDCl₃) δ 7.02 (dd, J=7.7, 5.2 Hz, 1H), 6.82 (d, J=4.3 Hz, 1H), 6.79(d, J=4.4 Hz, 1H), 6.40 (dd, J=9.7, 7.7 Hz, 1H), 4.45 (q, J=7.2 Hz, 2H),1.41 (t, J=7.2 Hz, 4H). LC-MS (Method C): m/z (ES+), [M+H]⁺=242.0. HPLCt_(R)=3.04 m.

Intermediate B. Ethyl 8-fluoroindolizine-5-carboxylate

CuCl (0.760 g, 7.67 mmol) was added to a solution of ethyl5-fluoro-6-prop-1-ynyl-pyridine-2-carboxylate (3.18 g, 15.4 mmol) in a7:1 mixture of degassed DMA (48.0 mL) and NEt₃ (6.85 mL, 49.1 mmol) at23° C. under nitrogen. The mixture was stirred at 130° C. for 17 h, andfiltered through Celite. The filtrate was diluted with EtOAc (250 mL)and water (250 mL). The aqueous phase was extracted with EtOAc (3×250mL), and the combined organic phases were washed with brine (250 mL),dried (MgSO₄), filtered, and concentrated under reduced pressure. Theproduct was purified by silica gel chromatography (80 g cartridge) withhexane and EtOAc (0-20%) to provide the title compound as a solid (1.68g, 53%). ¹H NMR (500 MHz, CDCl₃) δ 8.74 (ddd, J=3.9, 2.8, 1.4 Hz, 1H),7.61 (dd, J=8.0, 5.5 Hz, 1H), 6.91 (dd, J=4.1, 2.8 Hz, 1H), 6.83 (dd,J=4.1, 1.4 Hz, 1H), 6.40 (dd, J=9.7, 8.0 Hz, 1H), 4.43 (q, J=7.1 Hz,2H), 1.43 (t, J=7.1 Hz, 3H). LC-MS (Method C): m/z (ES+), No ionization.HPLC t_(R)=1.96 m.

Intermediate A. Ethyl 5-fluoro-6-prop-1-ynyl-pyridine-2-carboxylate

DIPEA (8.37 mL, 48.1 mmol) and 1M TBAF in THF (28.8 mL, 28.8 mmol) wereadded to a mixture of ethyl 6-bromo-5-fluoro-pyridine-2-carboxylate(5.96 g, 24.0 mmol), 1-(trimethylsilyl)-1-propyne (4.27 mL, 28.8 mmol),CuI (0.690 g, 3.60 mmol), and PdCl₂(PPh₃)₂ (1.69 g, 2.40 mmol) indegassed toluene (225 mL) at 23° C. under nitrogen. The mixture wasstirred for 16 h, and then diluted with Et₂O (250 mL) and saturatedNH₄Cl (150 mL). The aqueous phase was extracted with Et₂O (3×250 mL),and the combined organic phases were dried (MgSO₄), filtered, andconcentrated under reduced pressure. The product was purified by silicagel chromatography (120 g cartridge) with hexane and EtOAc (0-30%) toprovide the title compound as a solid (3.21 g, 65%). ¹H NMR (500 MHz,CDCl₃) δ 8.06 (dd, J=8.6, 4.0 Hz, 1H), 7.54-7.42 (m, 1H), 4.46 (q, J=7.1Hz, 2H), 2.14 (d, J=0.9 Hz, 3H), 1.42 (t, J=7.1 Hz, 3H). LC-MS (MethodC): m/z (ES+), [M+H]⁺=208.1. HPLC t_(R)=2.60 min.

Example 62.(4-Fluoro-1-methyl-1H-indazol-7-yl)(1H-imidazol-2-yl)methanol

2.50 M nBuLi in THF (0.260 mL, 0.640 mmol) was added to a mixture of1-(diethoxymethyl)imidazole (109 mg, 0.640 mmol) in THF (1.00 mL) at−45° C., and the mixture was stirred for 15 m maintaining thetemperature between −45° C. to −40° C. The mixture was cooled to −60°C., and a solution of 4-fluoro-1-methyl-indazole-7-carbaldehyde (57.0mg, 0.320 mmol) in THF (1.00 mL) was added. The mixture was stirred for10 m at −60° C. and warmed to 0° C. over 1 h. The mixture was dilutedwith 0.25 M HCl (5.00 mL) and EtOAc (5.00 mL) at 0° C. and stirred at23° C. for 10 m. The organic phase was extracted with 0.250 M HCl(3×10.0 mL), and the combined aqueous phases were diluted with sat.NaHCO₃ (20.0 mL) and extracted with EtOAc (3×50.0 mL). The combinedorganic phases were washed with brine (50.0 mL), dried over MgSO₄,filtered, and concentrated under reduced pressure. The product waspurified by silica gel chromatography (4 g cartridge) eluting with DCMand MeOH (0-10%) to provide the title compound as a solid (4.35 mg, 6%):¹H NMR (500 MHz, DMSO) δ 12.10 (s, 1H), 8.13 (s, 1H), 7.29 (dd, J=8.0,5.3 Hz, 1H), 6.94 (br, 1H), 6.86 (dd, J=9.8, 8.0 Hz, 2H), 6.51 (d, J=4.5Hz, 1H), 6.35 (d, J=4.5 Hz, 1H), 4.11 (s, 3H). LC-MS (Method C): m/z(ES+), [M−H₂O+H]⁺=229.0. HPLC t_(R)=1.26 min.

Intermediate D. 4-Fluoro-1-methyl-indazole-7-carbaldehyde

A solution of (4-fluoro-1-methyl-indazol-7-yl)methanol (50.0 mg, 0.280mmol) in CHCl₃ (1.00 mL) was added drop-wise to a mixture of MnO₂ (121mg, 1.39 mmol) in CHCl₃ (1.00 mL) at 0° C. The mixture was refluxed for3.5 h, and filtered through a pad of celite. The solid was washed withDCM, and the filtrate was concentrated under reduced pressure. Theproduct was purified by silica gel chromatography (4 g cartridge)eluting with hexane and EtOAc (0-30%) to provide the title compound as asolid (40.0 mg, 81%): ¹H NMR (500 MHz, CDCl₃) δ ppm 10.09 (s, 1H), 8.15(s, 1H), 7.86 (dd, J=8.1, 5.1 Hz, 1H), 6.92 (dd, J=8.8, 8.1 Hz, 1H),4.50 (s, 3H). LC-MS (Method C): m/z (ES+), No ionization. HPLCt_(R)=1.58 min.

Intermediate C. (4-Fluoro-1-methyl-indazol-7-yl)methanol

2.00M LAH in THF (0.220 mL, 0.440 mmol) was added to a mixture of ethyl4-fluoro-1-methyl-indazole-7-carboxylate (98.0 mg, 0.440 mmol) in THF(2.50 mL) at 0° C. under nitrogen. The mixture was warmed to 23° C. andstirred for 20 m. The mixture was diluted with acetone (1.00 mL) andsaturated Na/K tartrate (10.0 mL) at 0° C. and stirred for 5 m. Theaqueous phase was extracted with EtOAc (3×20.0 mL), and the combinedorganic phases were dried over MgSO₄, filtered, and concentrated underreduced pressure to provide the title compound as a solid (78.0 mg,98%). ¹H NMR (500 MHz, CDCl₃) δ 8.04 (s, 1H), 7.19 (dd, J=7.8, 5.0 Hz,1H), 6.69 (dd, J=9.5, 7.8 Hz, 1H), 4.98 (d, J=5.4 Hz, 2H), 4.39 (s, 3H),1.74 (t, J=5.8 Hz, 1H). LC-MS (Method C): m/z (ES+), No ionization. HPLCt_(R)=1.31 min.

Intermediate B. Ethyl 4-fluoro-1-methyl-indazole-7-carboxylate

Iodomethane (20.1 uL, 0.320 mmol) was added to a suspension of Cs₂CO₃(105 mg, 0.320 mmol) and ethyl 4-fluoro-1H-indazole-7-carboxylate (56.0mg, 0.270 mmol) in DMF (1.00 mL), and the mixture was stirred at 23° C.for 2.5 h. Water (10.0 mL) was added, and the aqueous phase wasextracted with EtOAc (3×10.0 mL). The combined organic phases werewashed with brine (20.0 mL), dried (MgSO₄), filtered, and concentratedunder reduced pressure. The product was purified by silica gelchromatography (12 g cartridge) with hexane and EtOAc (0-50%) to providethe title compound as a solid (36 mg, 60%). ¹H NMR (500 MHz, CDCl₃) δ8.11 (s, 1H), 7.94 (dd, J=8.2, 5.2 Hz, 1H), 6.77 (dd, J=8.9, 8.2 Hz,1H), 4.43 (q, J=7.1 Hz, 2H), 4.28 (s, 3H), 1.43 (t, J=7.1 Hz, 3H). LC-MS(Method C): m/z (ES+), [M+H]⁺=222.9. HPLC t_(R)=1.98 m.

Intermediate A. Ethyl 4-fluoro-1H-indazole-7-carboxylate

Ethyl 2-amino-4-fluoro-3-methyl-benzoate (505 mg, 2.56 mmol) and KOAc(131 mg, 1.33 mmol) were added to anhydrous toluene (15.0 mL) undernitrogen. The mixture was heated to reflux, and Ac₂O (0.730 mL, 7.68mmol) was added. The mixture was stirred at reflux for 10 m, andisopentyl nitrite (0.570 mL, 4.23 mmol) was added over 1 h. Stirring wascontinued at reflux for 15 h. The mixture was cooled and filtered. Thefiltrate was concentrated under reduced pressure, and the residue waswashed with hexanes, water, and finally with hexanes to afford the titlecompound as a solid (347 mg, 65%). ¹H NMR (500 MHz, CDCl₃) δ 11.30 (s,1H), 8.20 (d, J=1.7 Hz, 1H), 8.07 (dd, J=8.2, 4.8 Hz, 1H), 6.87 (dd,J=9.4, 8.2 Hz, 1H), 4.48 (q, J=7.1 Hz, 2H), 1.47 (t, J=7.1 Hz, 3H).LC-MS (Method C): m/z (ES+), [M+H]⁺=208.9. HPLC t_(R)=1.86 min.

Example 63.(3-Ethyl-7-fluorobenzofuran-4-yl)(1H-1,2,4-triazol-5-yl)methanol

Hydrogen chloride in EtOAc (excess) was added to(3-ethyl-7-fluorobenzofuran-4-yl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)methanol(150 mg, 0.38 mmol) in EtOAc (10 mL) under nitrogen. The resultingsolution was stirred at rt. for 16 hours. The solvent was removed underreduced pressure. The crude product was purified by flash C18-flashchromatography, elution gradient 5 to 80% MeCN in water. Pure fractionswere evaporated to dryness to afford(3-ethyl-7-fluorobenzofuran-4-yl)(1H-1,2,4-triazol-5-yl)methanol (30.0mg, 30.0%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.26-1.35 (m,3H), 2.05 (s, 0.1H), 2.76-2.94 (m, 2H), 6.46 (s, 1H), 7.03-7.07 (m, 1H),7.20-7.23 (m, 1H), 7.63 (s, 1H), 8.17 (s, 1H). LC-MS (Method A): m/z(ES+), [M+H]+=262.3; acid, HPLC t_(R)=1.560 min.

Intermediate B.(3-Ethyl-7-fluorobenzofuran-4-yl)(14(2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)methanol

3-Ethyl-7-fluorobenzofuran-4-carbaldehyde (450 mg, 2.34 mmol) was addedto 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole (933 mg, 4.68mmol) and n-butyllithium (1,967 mL, 4.92 mmol) in THF (10 mL) at −78° C.over a period of 1 hour under nitrogen. The resulting mixture wasstirred at −78° C. for 30 minutes. The reaction mixture was quenchedwith saturated NH₄Cl (5 mL), extracted with EtOAc (2×10 mL), the organiclayer was dried over Na₂SO₄, filtered and evaporated to afford whiteliquid. The crude product was purified by flash C18-flashchromatography, elution gradient 5 to 100% MeCN in water. Pure fractionswere evaporated to dryness to afford(3-ethyl-7-fluorobenzofuran-4-yl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)methanol(150 mg, 16.36%) as a white liquid. ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.66(s, 1H), 7.82 (d, J=1.4 Hz, 1H), 7.36 (dd, J=8.4, 4.5 Hz, 1H), 7.22 (dd,J=10.8, 8.4 Hz, 1H), 6.56 (d, J=5.8 Hz, 1H), 6.41 (d, J=5.8 Hz, 1H),5.65 (d, J=10.8 Hz, 1H), 5.43 (d, J=10.8 Hz, 1H), 3.55-3.38 (m, 2H),3.18 (d, J=5.2 Hz, 1H), 2.58 (ddt, J=15.7, 8.4, 6.8 Hz, 1H), 2.41 (ddt,J=14.6, 8.9, 7.3 Hz, 1H), 1.15 (t, J=7.4 Hz, 3H), 0.81 (dddd, J=45.9,13.7, 10.6, 6.1 Hz, 2H). LC-MS (Method A): m/z (ES+), [M+H]+=392; acid,HPLC t_(R)=0.987 min.

Intermediate A. 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole

SEM-Cl (6.93 mL, 39.09 mmol) was added dropwise to 1H-1,2,4-triazole (3g, 43.44 mmol) and NaH (2.085 g, 52.12 mmol) in THF (100 mL) at 0° C.over a period of 20 minutes under nitrogen. The resulting mixture wasstirred at rt. for 16 hours. The reaction mixture was quenched with ice(25 mL), extracted with EtOAc (2×25 mL), the organic layer was driedover Na₂SO₄, filtered and evaporated to afford white solid. The crudeproduct was purified by flash silica chromatography, elution gradient 0to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole (2.00 g, 23.1%)as a white solid. ¹H NMR (300 MHz, DMSO-d6) δ ppm 8.68 (s, 1H), 5.43 (s,1H), 3.56-3.43 (m, 1H), 0.92-0.77 (m, 1H).

Example 64.(4-Fluoro-2-(pyrrolidin-1-yl)phenyl)(1H-1,2,4-triazol-5-yl)methanol

Example 64 was prepared in analogy to Example 63 using4-fluoro-2-(pyrrolidin-1-yl)benzaldehyde and1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole. ¹H NMR (300 MHz,CDCl₃) δ ppm 8.01 (s, 1H), 7.24-7.33 (m, 1H), 6.94 (dd, J=2.54, 10.64Hz, 1H), 6.84 (dt, J=2.64, 8.19 Hz, 1H), 6.26 (s, 1H), 3.00-3.28 (m,4H), 1.92-2.10 (m, 4H). LC-MS (Method B): LC-MS (Method A): m/z (ES+),[M+H]+=263; acid, HPLC t_(R)=0.43 min.

Example 65. (4-Fluoro-2-(thiazol-2-yl)phenyl)(1H-imidazol-2-yl)methanol

Prepared in analogous fashion to Example 33. ¹H NMR (400 MHz, CD₃OD) δppm 6.45-6.50 (m, 1H), 7.17-7.23 (m, 2H), 7.32-7.37 (m, 1H), 7.53-7.56(m, 1H), 7.76-7.77 (m, 2H), 7.96-7.97 (m, 1H), 8.35 (s, 1H). LC-MS(Method A): m/z (ES+), [M+H]+=276.3; acid, HPLC t_(R)=1.312 min.

Example 66.[7-Fluoro-3-(1-methylcyclopropyl)benzofuran-4-yl]-(1H-imidazol-2-yl)methanol

1-(Diethoxymethyl)imidazole (81.9 mg, 0.480 mmol) in THF (1.00 mL) wascooled to −45° C. and 2.5M n-BuLi in THF (0.190 mL, 0.480 mmol) wasadded drop-wise. The mixture was stirred at −45° C. for 20 m. Themixture was cooled to −60° C., and a solution of7-fluoro-3-(1-methylcyclopropyl)benzofuran-4-carbaldehyde (50.0 mg,0.230 mmol) in THF (1.00 mL) was added drop-wise. The solution waswarmed to 0° C. over 1 h. 0.1M HCl (5.00 mL) was added, and the mixturewas warmed to 23° C. and stirred for 10 m. EtOAc (5.00 mL) was added.The organic phase was extracted with 0.1M HCl (2×5.00 mL), and thecombined aqueous phases were diluted with sat. NaHCO₃ (10.0 mL). Theaqueous mixture was extracted with EtOAc (3×25.0 mL), and the combinedorganic phases were washed with brine (25.0 mL), dried over MgSO₄,filtered and concentrated under reduced pressure. The product waspurified by Waters HPLC (Gemini NX, 150×30, 5 micron, C-18 column),eluting isocratically with a mixture of water and MeCN (50%), containing0.1% of (NH₄)₂CO₃ to provide the title compound as a solid (37 mg, 56%).¹H NMR (500 MHz, DMSO) δ 12.03 (s, 1H), 7.94 (s, 1H), 7.28 (dd, J=8.5,4.6 Hz, 1H), 7.19 (dd, J=10.7, 8.5 Hz, 1H), 7.02 (s, 1H), 6.73 (s, 1H),6.68 (d, J=4.2 Hz, 1H), 6.13 (d, J=4.2 Hz, 1H), 1.42 (s, 3H), 1.01-0.87(m, 1H), 0.87-0.79 (m, 1H), 0.79-0.72 (m, 1H), 0.72-0.59 (m, 1H). LC-MS(Method C): m/z (ES+), [M+H]⁺=287.1. HPLC t_(R)=1.57 m.

Intermediate F.7-Fluoro-3-(1-methylcyclopropyl)benzofuran-4-carbaldehyde

MnO₂ (114 mg, 1.31 mmol) was added to a mixture of[7-fluoro-3-(1-methylcyclopropyl)benzofuran-4-yl]methanol (72.0 mg,0.330 mmol) in CHCl₃ (2.00 mL) at 23° C. under nitrogen. The mixture wasrefluxed for 18 h, and filtered through a pad of Celite. The solid waswashed with DCM, and the filtrate was concentrated under reducedpressure. The product was purified by silica gel chromatography (12 gcartridge) eluting with hexane and EtOAc (0-15%) to provide the titlecompound as a solid (52.0 mg, 73%). ¹H NMR (500 MHz, CDCl₃) δ 10.87 (d,J=0.6 Hz, 1H), 7.95 (dd, J=8.6, 4.6 Hz, 1H), 7.67 (s, 1H), 7.20-7.06 (m,1H), 1.45 (s, 3H), 0.99-0.89 (m, 2H), 0.89-0.79 (m, 2H). LC-MS (MethodC): m/z (ES+), No ionization. HPLC t_(R)=2.54 m.

Intermediate E.[7-Fluoro-3-(1-methylcyclopropyl)benzofuran-4-yl]methanol

1.00 M LAH in THF (0.370 mL, 0.370 mmol) was added to a cooled solutionof methyl 7-fluoro-3-(1-methylcyclopropyl)benzofuran-4-carboxylate (92.0mg, 0.370 mmol) in THF (1.00 mL) at 0° C. under nitrogen. The mixturewas stirred at 0° C. for 15 m and diluted with acetone (0.500 mL) and asat. solution of K/Na tartrate (10.0 mL). Water (10.0 mL) was added, andthe aqueous phase was extracted with EtOAc (3×25.0 mL). The combinedorganic phases were washed with brine (30.0 mL), dried (MgSO₄),filtered, and concentrated under reduced pressure to afford the titlecompound as an oil (72.0 mg; 88%). ¹H NMR (500 MHz, CDCl₃) δ 7.51 (s,1H), 7.29 (dd, J=8.3, 4.4 Hz, 1H), 7.03 (dd, J=10.3, 8.3 Hz, 1H), 5.17(s, 2H), 1.71 (br, 1H), 1.44 (s, 3H), 0.91-0.83 (m, 2H), 0.79-0.72 (m,2H). LC_MS (Method C): m/z (ES+), No ionization. HPLC t_(R)=2.29 m.

Intermediate D. Methyl7-fluoro-3-(1-methylcyclopropyl)benzofuran-4-carboxylate

1.60 M MeLi in Et₂O (0.700 mL, 1.11 mmol) was added drop-wise to acooled solution of methyl2-bromo-4-fluoro-3-[2-(1-methylcyclopropyl)-2-oxo-ethoxy]benzoate (320mg, 0.930 mmol) in THF (92.0 mL) at −78° C. The mixture was stirred at−78° C. for 30 m. Additional 1.60 M MeLi in Et₂O (0.280 mL, 0.440 mmol)was added at −78° C. The mixture was warmed to 0° C. and diluted withsat. NH₄Cl (30 mL). The mixture was partially concentrated under reducedpressure to remove THF, and water (20.0 mL) was added. The aqueous phasewas extracted with EtOAc (3×50.0 mL), and the combined organic phaseswere washed with brine (50.0 mL), dried over MgSO₄, filtered andconcentrated under reduced pressure. The residue was dissolved intoluene (9.00 mL), and 4 Å molecular sieves and p-TSA monohydrate (44.1mg, 0.230 mmol) were added. The mixture was heated at reflux for 45 m.After cooling to room temperature, the mixture was filtered, and thefiltrate was concentrated under reduced pressure. The product waspurified by silica gel chromatography (12 g cartridge), eluting withhexane and EtOAc (0-15%) to provide the title compound as an oil (99.0mg, 43%). ¹H NMR (500 MHz, CDCl₃) δ 7.70 (dd, J=8.5, 4.6 Hz, 1H), 7.61(s, 1H), 7.04 (dd, J=9.8, 8.5 Hz, 1H), 3.96 (s, 3H), 1.38 (s, 3H),0.88-0.76 (m, 2H), 0.74-0.66 (m, 2H). LC-MS (Method C): m/z (ES+), Noionization. HPLC t_(R)=2.60 m.

Intermediate C. Methyl2-bromo-4-fluoro-3-[2-(1-methylcyclopropyl)-2-oxo-ethoxy]benzoate

2-Bromo-1-(1-methylcyclopropyl)ethanone (206 mg, 1.16 mmol) and K₂CO₃(210 mg, 1.52 mmol) were added to a solution of methyl2-bromo-4-fluoro-3-hydroxy-benzoate (252 mg, 1.01 mmol) in acetone (5.00mL). The mixture was heated to 60° C. for 18 h. The mixture was filteredthrough Celite, and the solid was washed with EtOAc. The filtrate wasconcentrated under reduced pressure. The product was purified by silicagel chromatography (25 g cartridge), eluting with EtOAc and hexanes(0-25%) to provide the title compound as an oil (0.332 g, 95%). ¹H NMR(500 MHz, CDCl₃) δ 7.52 (dd, J=8.7, 5.3 Hz, 1H), 7.09 (dd, J=10.2, 8.7Hz, 1H), 4.95 (d, J=1.1 Hz, 2H), 3.92 (s, 3H), 1.39 (s, 3H), 1.38-1.35(m, 2H), 0.81-0.77 (m, 2H). LC-MS (Method C): m/z (ES+), [M+H]⁺=345.0.HPLC t_(R)=2.31 min.

Intermediate B. 2-Bromo-1-(1-methylcyclopropyl)ethanone

A solution of bromine (0.780 mL, 15.3 mmol) in DCM (7.50 mL) was addeddrop-wise to a cooled solution of methyl 1-methylcyclopropyl ketone(1.68 mL, 15.3 mmol) in MeOH (12.0 mL) at 0° C. The mixture was stirredfor 1 h and poured onto ice. The aqueous phase was extracted with DCM(4×20.0 ml), and the combined organic phases were dried over Na₂SO₄,filtered, and concentrated under reduced pressure to provide the titlecompound (2.55 g, 94%) as an oil. ¹H NMR (500 MHz, CDCl₃) δ 4.01 (s,2H), 1.45 (d, J=0.6 Hz, 3H), 1.37-1.32 (m, 2H), 0.86-0.82 (m, 2H). LC_MS(Method C): m/z (ES+), No ionization. HPLC t_(R)=2.02 min.

Intermediate A. Methyl 2-bromo-4-fluoro-3-hydroxy-benzoate

A solution of bromine (0.510 mL, 10.0 mmol) in DCM (5.00 mL) was addeddrop-wise to a cooled solution of tert-butylamine (2.10 mL, 20.0 mmol)in DCM (20.0 mL) at −78° C. The mixture was stirred at −78° C. coveredwith aluminum foil for 1 h. A solution of methyl4-fluoro-3-hydroxy-benzoate (1.70 g, 10.0 mmol) in DCM (20.0 mL) wasadded drop-wise at −78° C. The mixture was stirred at −78° C., coveredwith aluminum foil, and slowly warmed to 23° C. for 18 h. The mixturewas filtered, and 1N HCl (30.0 mL) was added to the filtrate. Theaqueous phase was extracted with DCM (2×25.0 mL). The combined organicphases were washed with brine (30.0 mL), dried over MgSO₄, filtered, andconcentrated under reduced pressure. The residue was diluted with 1N HCl(25.0 mL), and the aqueous phase was extracted with DCM (3×25.0 mL). Thecombined organic phases were washed with brine (25.0 mL), dried overMgSO₄, filtered, and concentrated under reduced pressure to provide thetitle compound as a solid (1.45 g; 58%). ¹H NMR (500 MHz, CDCl₃) δ 7.49(dd, J=8.7, 5.4 Hz, 1H), 7.18-7.05 (m, 1H), 5.90 (d, J=1.7 Hz, 1H), 3.93(s, 3H). LC MS (Method C): m/z (ES+), No ionization. HPLC t_(R)=1.89 m.

Assay Methods:

IPone Assay:

Protocol for Testing Compounds for PAR2 Antagonist Activity Using anIP-One HTRF Assay

Inositol monophosphate (IP1) production were measured in 1321N1 cellsstably expressing human PAR2 using an IP-One HTRF assay kit (Cisbio). 80nl of compound in 100% DMSO were added in white small-volume 384-wellplates using an Echo 555 (Labcyte) and were incubate for 30 min at 37°C. with 4 μl of cells (15,000 cells per well) in stimulation buffer(HBSS with 20 mM HEPES, pH 7.4). IP1 production was initiated byaddition of 4 μl of 140 μM SLIGRL-NH₂ (SEQ ID NO.: 4) in stimulationbuffer supplemented with 100 mM LiCl. After 60 min at 37° C. cells werelysed and IP1 concentrations were detected according to themanufacturers protocol (Cisbio). Data were normalized to IP1concentrations using a IP1 standard curve according to the manufacturersprotocol (Cisbio).

Trypin Activated FLPR Assay:

Protocol for Testing Compounds for PAR2 Antagonist Activity Using a Ca²⁺Mobilization Assay

Calcium mobilization was measured using 1321N1 cells stably expressinghuman PAR2. Cells were seeded in 384-well plates at 4,000 cells per wellin 20 μl DMEM with Glutamax supplemented with 10% FBS and incubated for18-24 h at 37° C., 5% CO₂ and 95% humidity. Cells were loaded with 20 μlFluo-8 NW calcium dye (Cat: 36316, AAT Bioquest) and kept at 37° C. for30 min prior to addition of 10 μl compound prepared in 20 mM HEPES pH7.4, HBSS, 2.5% DMSO, 0.1% BSA and 6 μM Vorapaxar (to block Trypsininduced activity of PAR1). The addition was done using a FLIPR^(TETRA)(384-well head, Molecular Devices) and the response was readsimultaneously to detect any agonist activity. The cells were incubatedfor 30 min at room temperature with the compounds and were thenevaluated for antagonist activity by addition of 10 μl 234 nM Trypsinprepared in 20 mM HEPES pH 7.4, HBSS and 0.1% BSA and simultaneousdetection of calcium mobilization using the FLIPR^(TETRA).

TABLE 1 IPone and FLPR (Trypsin) assay data hPAR2 IPpone hPAR2 FLPR(Trypsin) Example IC₅₀ (μM) IC₅₀ (μM) 1 2.93 nm 2 >100 >41 3 1.29 3.92 46.27 16.57 5 5.18 13.7 6 5.0 9.57 7 11.5 7.85 8 5.64 5.10 9 9.66 6.26 101.66 5.90 11 >41 >77 12 4.0 4.9 13 5.45 12.4 14 1.52 16.9 15 >100 >41 160.96 10.1 17 1.05 8.75 18 0.90 4.28 19 93 >100 20 4.5 18.6 21 6.40 40.322 4.60 20 23 7.21 25.4 24 6.73 16.3 25 6.88 22.0 26 3.87 nm 276.96 >41.6 28 4.91 30.3 29 13.1 >41.6 30 4.67 11.6 31 4.32 >41 32 14.330.6 33 3.6 16.8 34 0.30 1.90 35 0.2 1.61 36 >100 >41 37 0.97 3.27 381.91 13.9 39 13.2 nm 40 0.75 4.90 41 26 2.19 42 0.33 3.09 43 0.86 4.5844 6.54 >41 45 0.63 6.07 46 2.17 14.5 47 2.12 4.91 48 >33.3 >41.6 49 nmnm 50 >33.3 >41 51 0.60 1.50 52 0.97 3.27 53 1.63 5.42 54 1.45 6.15 551.39 2.64 56 >100 >41.6 57 1.65 9.03 58 7.21 >41.6 59 9.23 6.73 60 0.98.13 61 1.90 3.1 62 3.38 nm 63 1.23 15.6 64 4.06 20 65 7.79 18.3 66 nmnmBinding Studies

In some embodiments, the application provides compounds that bind to asite distinct from the PAR1 Vorapaxar site using crystallographytechniques on a mutant form of the PAR2 receptor.

The structure of PAR1 in complex with Vorapaxar showed that the ligandbinds in a peripheral pocket close to the extracellular surface of PAR1(Zhang, C. et al. Nature 2012, 492, 387-392. Whilst vorapaxar exhibithigh selectivity against PAR2 nearly all residues involved in theinteractions are conserved. Mutational studies have shown Glu260 andAsp256 of extra cellular loop 2 (ECL2) to be important for binding theactivating peptide. Both of these residues are conserved in PAR2 (Glu232and Asp228). The Vorapaxar pocket is therefore believed to be theorthosteric site for related protease activated receptors.

A crystal structure with Example 3 in complex with PAR2, revealed thatthe ligand binds in a novel allosteric pocket, 8 Å away from theVorapaxar binding site identified in the PAR1 structure (FIG. 1). Thepocket is completely buried in the receptor (FIG. 2) which is consistentwith the long dissociation rates of the compounds in this series. Theligand is situated in a relatively rigid part of the protein near thedisulphide bridge in between transmembrane 3 (TM3) and ECL2. It makespolar interactions with Asp228, Tyr 82 and His135 (FIG. 3). Based onstructural data, the allosteric and the orthosteric pockets in PAR2 areclearly separated. None of the ligands tested in the Example 3 serieshave demonstrated activity against PAR1 (β-arrestin type assay byDiscoverX, Example 3 IC₅₀>50 μM, Example 35 >50 μM).

FLPR Dissociation Rate Assay: Protocol for Testing Compounds for PAR2Mean Residence Time

The FLPR assay outlined above utilized the same cell line andcell-handling protocols, but was modified in the following ways: Thecells were incubated with compound at various time points (60 min, 120min, 180 min and 240 min) at which point the cells were washed. Fluo-8NW calcium dye (Cat: 36316, AAT Bioquest) was added similar to theprotocol described above, one hour before the addition of agonist. Thepeptide agonist SLIGLR-NH₂ (EC₈₀) was used in place of trypsin.

TABLE 2 FLPR dissociation rate assay data Example FLPR Residence timet_(1/2) (min) 3 62 16 161 42 119 47 31

The invention claimed is:
 1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein: R³ is F; X is CH; Y is C or N; and Z is C or N, wherein Y and Z are not both N, and (1) when both Z and Y are C, the bond “

” is a double bond, and R¹ is selected from C₂₋₆ alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, and heteroaryl, wherein R¹ is substituted with 0-3 R, wherein each occurrence of R is independently selected from alkyl; cycloalkyl; halo; —OH; alkoxy; —CN; —NR^(a)R^(b)′, —N(R^(a))C(O) alkyl; —N(R^(a))CO₂alkyl; —N(R^(a))SO₂alkyl; —C(O)alkyl; —CO₂H; —CO₂alkyl; —CONR^(a)R^(b); —SO₂alkyl; and —SO₂NR^(a)R^(b); wherein R^(a) and R^(b) are independently for each occurrence H or alkyl; R² is H or halogen; or R¹ and R² may be taken together with the atoms to which they are bound to form a 3- to 10-membered aromatic or non-aromatic monocyclic ring having 0-3 heteroatoms or heteroatom groups independently selected from N, NH, O, S, SO, and SO₂, wherein said ring is substituted with 0-3 R, and wherein said ring is optionally fused to a C₆₋₁₀aryl, 5- to 10-membered heteroaryl, C₃₋₁₀cycloalkyl, or a 3- to 10-membered heterocyclyl, wherein said C₆₋₁₀aryl, 5- to 10-membered heteroaryl, C₃₋₁₀cycloalkyl, or a 3- to 10-membered heterocyclyl is substituted with 0-3 R, wherein each occurrence of R is independently selected from alkyl; cycloalkyl; halo; —OH; alkoxy; —CN; —NR^(a)R^(b;), —N(R^(a))C(O) alkyl; —N(R^(a))CO₂alkyl; —N(R^(a))SO₂alkyl; —C(O)alkyl; —CO₂H; —CO₂alkyl; —CONR^(a)R^(b); —SO₂alkyl; and —SO₂NR^(a)R^(b); wherein R^(a) and R^(b) are independently for each occurrence H or alkyl; or (2) when one of Z and Y is N, the other is C, the bond “

” is a single bond, and R¹ and R² are taken together with the atoms to which they are bound to form a 3- to 10-membered aromatic or non-aromatic monocyclic ring having 1-3 heteroatoms or heteroatom groups independently selected from N, NH, O, S, SO, and SO₂, wherein said ring is substituted with 0-3 R, and wherein said ring is optionally fused to a C₆₋₁₀aryl, 5- to 10-membered heteroaryl, C₃₋₁₀cycloalkyl, or a 3- to 10-membered heterocyclyl, wherein said C₆₋₁₀aryl, 5-to 10-membered heteroaryl, C₃₋₁₀cycloalkyl, or a 3- to 10-membered heterocyclyl is substituted with 0-3 R, wherein each occurrence of R is independently selected from alkyl; cycloalkyl; halo; —OH; alkoxy; —CN; —NR^(a)R^(b;), —N(R^(a))C(O) alkyl; —N(R^(a))CO₂alkyl; —N(R^(a))SO₂alkyl; —C(O)alkyl; —CO₂H; —CO₂alkyl; —CONR^(a)R^(b); —SO₂alkyl; and —SO₂NR^(a)R^(b); wherein R^(a) and R^(b) are independently for each occurrence H or alkyl.
 2. The compound of claim 1, wherein both Z and Y are C and R¹ is C₂₋₆ alkyl optionally substituted with 0-3 R.
 3. The compound of claim 2, wherein R² is —H.
 4. The compound of claim 1, wherein the structure

is selected from:

wherein R⁵ is —H or —C₁₋₃alkyl, n is selected from 0-3.
 5. The compound of claim 1, wherein the structure

is selected from:


6. The compound of claim 1, wherein the structure

is selected from:


7. The compound of claim 1 which is selected from the group consisting of: (4-Fluoro-2-propylphenyl)(1H-imidazol-2-yl)methanol; (R)-(4-fluoro-2-propylphenyl)(1H-imidazol-2-yl)methanol; (S)-(4-Fluoro-2-propylphenyl)(1H-imidazol-2-yl)methanol; (2-Cyclopentenyl-4-fluorophenyl)(1H-imidazol-2-yl)methanol; (2-Cyclopentyl-4-fluorophenyl)(1H-imidazol-2-yl)methanol; (2-Cyclobutyl-4-fluorophenyl)(1H-imidazol-2-yl)methanol; (E)-(4-Fluoro-2-(prop-1-enyl)phenyl)(1H-imidazol-2-yl)methanol; (Z)-(4-Fluoro-2-(prop-1-enyl)phenyl)(1H-imidazol-2-yl)methanol; (3,4-Difluoro-2-propylphenyl)(1H-imidazol-2-yl)methanol; (R)-(3,4-Difluoro-2-propylphenyl)(1H-imidazol-2-yl)methanol; (S)-(3,4-Difluoro-2-propylphenyl)(1H-imidazol-2-yl)methanol; (4-Fluoro-2-(pyrrolidin-1-yl)phenyl)(1H-imidazol-2-yl)methanol; (R)-(4-Fluoro-2-(pyrrolidin-1-yl)phenyl)(1H-imidazol-2-yl)methanol; (S)-(4-Fluoro-2-(pyrrolidin-1-yl)phenyl)(1H-imidazol-2-yl)methanol; (2-(2,5-dihydro-1H-pyrrol-1-yl)-4-fluorophenyl)(1H-imidazol-2-yl)methanol; (R)-(2-(2,5-dihydro-1H-pyrrol-1-yl)-4-fluorophenyl)(1H-imidazol-2-yl)methanol; (S)-(2-(2,5-dihydro-1H-pyrrol-1-yl)-4-fluorophenyl)(1H-imidazol-2-yl)methanol; (2-(Azetidin-1-yl)-4-fluorophenyl)(1H-imidazol-2-yl)methanol; (3,4-Difluoro-2-(1H-pyrazol-1-yl)phenyl)(1H-imidazol-2-yl)methanol; (4-Fluoro-2-(1H-pyrazol-1-yl)phenyl)(1H-imidazol-2-yl)methanol; (4-Fluoro-2-(3-fluoro-3-methylazetidin-1-yl)phenyl)(1H-imidazol-2-yl)methanol; (4-Fluoro-2-(3-methylazetidin-1-yl)phenyl)(1H-imidazol-2-yl)methanol; (4-Fluoro-2-((S)-3-fluoropyrrolidin-1-yl)phenyl)(1H-imidazol-2-yl)methanol; (4-Fluoro-2-((R)-3-fluoropyrrolidin-1-yl)phenyl)(1H-imidazol-2-yl)methanol; (2-(3,3-Difluoropyrrolidin-1-yl)-4-fluorophenyl)(1H-imidazol-2-yl)methanol; (4-Fluoro-2-((R)-3-methylpyrrolidin-1-yl)phenyl)(1H-imidazol-2-yl)methanol; (2-(3-Azabicyclo[3.1.0]hexan-3-yl)-4-fluorophenyl)(1H-imidazol-2-yl)methanol; (2-(Bicyclo[3.1.0]hexan-1-yl)-4-fluorophenyl)(1H-imidazol-2-yl)methanol; (4-Fluoro-2-(oxazol-4-yl)phenyl)(1H-imidazol-2-yl)methanol; (4-Fluoro-2-(thiazol-4-yl)phenyl)(1H-imidazol-2-yl)methanol; (3-Ethyl-8-fluoroindolizin-5-yl)(1H-imidazol-2-yl)methanol; (R)-(3-Ethyl-8-fluoroindolizin-5-yl)(1H-imidazol-2-yl)methanol; (S)-(3-Ethyl-8-fluoroindolizin-5-yl)(1H-imidazol-2-yl)methanol; (8-Fluoro-3-methylindolizin-5-yl)(1H-imidazol-2-yl)methanol; (8-Fluoro-3-isopropylindolizin-5-yl)(1H-imidazol-2-yl)methanol; (3-Cyclopropyl-8-fluoroindolizin-5-yl)(1H-imidazol-2-yl)methanol; (3-Ethyl-7-fluorobenzofuran-4-yl)(1H-imidazol-2-yl)methanol; (R)-(3-Ethyl-7-fluorobenzofuran-4-yl)(1H-imidazol-2-yl)methanol; (S)-(3-Ethyl-7-fluorobenzofuran-4-yl)(1H-imidazol-2-yl)methanol; (3-Cyclopropyl-7-fluorobenzofuran-4-yl)(1H-imidazol-2-yl)methanol; (R)-(3-Cyclopropyl-7-fluorobenzofuran-4-yl)(1H-imidazol-2-yl)methanol; (S)-(3-Cyclopropyl-7-fluorobenzofuran-4-yl)(1H-imidazol-2-yl)methanol; (3-Ethyl-7-fluorobenzo[b]thiophen-4-yl)(1H-imidazol-2-yl)methanol; (R)-(3-Ethyl-7-fluorobenzo[b]thiophen-4-yl)(1H-imidazol-2-yl)methanol; (S)-(3-Ethyl-7-fluorobenzo[b]thiophen-4-yl)(1H-imidazol-2-yl)methanol; (7-Fluoro-3-methylbenzofuran-4-yl)(1H-imidazol-2-yl)methanol; (4-Fluorodibenzo[b,d]furan-1-yl)(1H-imidazol-2-yl)methanol; (4-Fluoro-1-methyl-1H-indol-7-yl)(1H-imidazol-2-yl)methanol; (R)-(4-Fluoro-1-methyl-1H-indol-7-yl)(1H-imidazol-2-yl)methanol; (S)-(4-Fluoro-1-methyl-1H-indol-7-yl)(1H-imidazol-2-yl)methanol; (1-Ethyl-4-fluoro-1H-indol-7-yl)(1H-imidazol-2-yl)methanol; (4-Fluoro-8-methylnaphthalen-1-yl)(1H-imidazol-2-yl)methanol; (1-Ethyl-5-fluoro-indolizin-8-yl)-(1H-imidazol-2-yl)methanol; (3-Chloro-8-fluoro-indolizin-5-yl)-(1H-imidazol-2-yl)methanol; (4-Fluoro-1-methyl-1H-indazol-7-yl)(1H-imidazol-2-yl)methanol; (4-Fluoro-2-(thiazol-2-yl)phenyl)(1H-imidazol-2-yl)methanol; [7-Fluoro-3-(1-methylcyclopropyl)benzofuran-4-yl]-(1H-imidazol-2-yl)methanol; and pharmaceutically acceptable salts thereof.
 8. The compound of claim 1, wherein the compound is selected from: (R)-(3,4-Difluoro-2-propylphenyl)(1H-imidazol-2-yl)methanol; (2-(3,3-Difluoropyrrolidin-1-yl)-4-fluorophenyl)(1H-imidazol-2-yl)methanol; (S)-(4-Fluoro-2-propylphenyl)(1H-imidazol-2-yl)methanol; (4-Fluoro-1-methyl-1H-indazol-7-yl)(1H-imidazol-2-yl)methanol; (3-Ethyl-7-fluorobenzo[b]thiophen-4-yl)(1H-imidazol-2-yl)methanol; (S)-(3-Ethyl-8-fluoroindolizin-5-yl)(1H-imidazol-2-yl)methanol; (R)-(4-Fluoro-1-methyl-1H-indol-7-yl)(1H-imidazol-2-yl)methanol; (4-Fluorodibenzo[b,d]furan-1-yl)(1H-imidazol-2-yl)methanol; (R)-(3-Ethyl-8-fluoroindolizin-5-yl)(1H-imidazol-2-yl)methanol; (3,4-Difluoro-2-propylphenyl)(1H-imidazol-2-yl)methanol; and pharmaceutically acceptable salts thereof.
 9. A pharmaceutical composition comprising (a) a compound of claim 1 and (b) a pharmaceutically acceptable excipient.
 10. A method of treating a disease or disorder mediated by PAR2 activity, comprising administering to a subject in need of such treatment an effective amount of at least one compound of claim
 1. 11. The method of claim 10, wherein the disease or disorder is pain, musculoskeletal inflammation, neuroinflammatory disorders, airway inflammation, itch, dermatitis, or colitis.
 12. A method of modulating the activity of PAR2, comprising contacting a cell comprising the PAR2 with an effective amount of at least one compound of claim
 1. 13. A method of treating a disease or disorder in a patient in need thereof, comprising administering a compound of claim 1, wherein the disease or disorder is pain, musculoskeletal inflammation, neuroinflammatory disorders, airway inflammation, itch, dermatitis, or colitis. 